Cardiovascular Research 1992;26:265-272
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Aortic input impedence and neurohormonal activation in patients with mild to moderate chronic congestive heart failure Eckhard P Kromer, Dietmar Elsner, Stephan R Holmer, Andreas Muntze, and Gunter A J Riegger Objective: The aim was to investigate the interrelation between pulsatile components (assessed by determination of aortic input impedance) and neurohormonal activation in chronic congestive heart failure. Methods: Aortic input impedance, plasma noradrenaline, renin, atrial natriuretic factor, and arginine vasopressin were measured in 20 patients with mild to moderate chronic congestive heart failure (coronary artery disease n=12, idiopathic dilated cardiomyopathy n=8). Results: Cardiac index [2.2(SEM 0.3) litre.min-'.m-'] and left ventricular ejection fraction [38(4)%] were reduced, and pulmonary wedge pressure was increased [2 l(2) mmHg]. Plasma concentrations of noradrenaline [462(62) p g m - l ] , renin [ 12(4) ng AI.ml.h-l], atrial natriuretic factor [408(64) p g d ] , and - to a slight degree - arginine vasopressin [ l.l(O.3) pg.ml-'] were increased. Characteristic impedance Z, [80(6) dyne.scrn-') and relative oscillatory aortic input pressure power [ 10(1 )%] - both reflecting the pulsatile components of left ventricular afterload - were within the normal range. There was no significant correlation between these variables and the degree of neurohormonal activation (r values: -0.05 to -0.35). Conclusions: The data show that in patients with mild to moderate chronic congestive heart failure there is no interrelationship between the degree of neurohormonal activation and pulsatile components of left ventricular afterload. This may indicate that in these stages of heart failure there are no trophic effects of stimulated neurohormonal systems on the physical properties of the great arteries.
C
ongestive heart failure is characterised by a primary abnormality in systolic and/or diastolic function of the heart. Secondarily a number of neurohormonal mechanisms are activated in order to preserve circulatory homeostasis, ie, to support systemic blood pressure, cardiac contractility, and glomerular filtration rate (table I). Neurohormonal activation, which may be found even in early congestive heart failure,' ' was originally viewed as a beneficial compensatory response. However, an abundant endogenous release of vasoconstrictor hormones may exert deleterious haemodynamic effects. The increase of left ventricular preload and afterload may accelerate progression of heart failure. The degree of neurohormonal activation reflects the severity of the heart failure, and may be a prognostic factor in such patients.'-' In addition to effects on vascular tone, noradrenaline, angiotensin 11, and arginine vasopressin may exert direct trophic effects on vascular smooth muscle cells in vitro.6-9 Furthermore, arterial wall sodium content may increase due to neurohormonal activation.'" Thus at least three different mechanisms might contribute to the increase in the loading conditions of the failing heart. However, it is difficult exactly to assess left ventricular afterload, which plays a crucial role in left ventricular function in congestive heart failure. Usually mean left ventricular ejection pressure or systemic vascular resistance are accepted as close reflections. Systemic vascular resistance represents the resistance to steady flow and as such is one component of afterload. It does not take
into account the pulsatile component of arterial hydraulic load. Aortic input impedance represents the vascular hydraulic load encountered by the ejecting left ventricle." Recent data from Hirooka et (11, obtained in an animal study, suggest that atrial natriuretic factor may directly dilate the aorta," thereby reducing the pulsatile component of left venticular afterload. This could be beneficial to the impaired left ventricle of patients with congestive heart failure. Thus neurohormonal activation may exert complex effects on steady and pulsatile components of left ventricular afterload. Steady components of left ventricular afterload usually show fair correlations with the degree of neurohormonal activation. The interrelation with pulsatile components, however, has not yet been investigated. In the present study we investigated neurohormonal activation and variables characterising left ventricular hydraulic load in patients with chronic mild to moderate congestive heart failure.
Methods Patietit population
We studied 20 patients (1 2 men, eight women, mean age 58 (SEM 3) years, range 52 to 68) with stable mild to moderate chronic congestive heart failure. Patients with a history of diabetes mellitus and/or arterial hypertension were excluded. The diagnosis of congestive heart failure was established using the patients' carefully obtained history along with
I1 Medizinische Klinik, Universitatsklinikum Regensburg, Franz-Joseph-StrauS-Allee 1 1, 8400 Regensburg, Germany: E P Kromer, D Elsner, S R Holmer, A Muntze, G A J Riegger. Correspondence to Professor Kromer.
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Table I Neurohormonal svstems activated in patients with chronic congestive heart failure. Vasoconstriction:
Vasodilatation:
Sympathetic nervous system Renin-angiotensin-aldosterone system Arginine vasopressin Endothelin- I Atrial natriuretic factor Prostaglandin IZ Prostaglandin EZ Endothelium derived relaxing factor Bradykinin Dopamine Vasoactive intestinal peptide
chest x ray examinations and echocardiographic and cardiac catheterisation data. The cause of congestive heart failure was coronary artery disease (n= 12) and idiopathic dilated cardiomyopathy (n=8). All patients had sinus rhythm, and none had significant mitral regurgitation or peripheral oedema. The mean duration of congestive heart failure was 3.7 years (range 1.2-6.3). Serum sodium concentration, total protein content, and packed cell volume were within the normal range in each patient. Written, informed consent was obtained from all patients before the study. The study protocol was approved by the ethics committee of the University of Wiirzburg. Study protocol
Except for digitalis all medication was discontinued 3 d prior to the study. On the day of the investigation digitalis was also withheld. The patients were in a fasting condition for 12 h. All investigations were performed between 9.00 and 10.00 hours to avoid confounding diurnal effects. Under local anaesthesia the right femoral vein and artery were cannulated. After a period of 1 h, blood was drawn from the pulmonary artery for determination of plasma noradrenaline, renin, arginine vasopressin and atrial natriuretic factor. Right heart catheterisation was performed using a 7 F Swan-Ganz balloon flotation catheter. Cardiac output was measured by thermodilution in triplicate. A Millar microtip catheter (SVPC-684-A, Millar, Houston, TX, USA), containing a velocity probe close to a pressure sensor, was advanced to the bulbus aortae. The velocity probe was energised by an 800 Hz square wave electromagnetic flow meter (Servomed, Hellige, Freiburg, Germany), and velocity signals were recorded at a 30 Hz filter setting. After repeated measurements of pressure and velocity, left ventriculograms were obtained in a right anterior oblique projection, and left ventricular ejection fraction was calculated from the left ventricular v01umes.'~
Data analysis Pressure and velocity signals were digitised along with the ECG, using a 12 bit analogue to digital converter (Data Translation 2814, Marlborough, MA, USA) at a sampling rate of 400 Hz. The data were stored on an IBM compatible personal computer. For ECG triggered signal averaging, 10 to 30 beats with optimal velocity configuration were superimposed (figs 1 and 2). No postectopic beats were included and only beats with RR intervals within 5% of the mean value were analysed. The averaged velocity signal was scaled to volumetric flow by setting the integrated area beneath the velocity signal equal to the simultaneously determined cardiac output. Thereafter the pressure and flow signals were subjected to fast Fourier transformation (15 harmonics). The respective pressure (Pn) and flow (Qn) moduli for each harmonic were used to derive the impedance modulus (Zn) as Pn/Qn, while impedance phase is the
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Figure I I7 non-consecutive beats from a patient with rnoderiitr chronic congestive heart failure superimposed io examine belit to beat variability in pressure (top) and velocity (bottom).
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Figure 2 Computer processed, signal averaged composite pressure (top) and velocity (bottom) waves derived from the 17 beats shown in jig 1.
difference of pressure and flow phase. The aortic input impedance spectrum was displayed as a plot of impedance modulus v frequency (fig 3). The 0 Hz or resistive term of the impedance spectrum corresponds to the systemic vascular resistance. Characteristic impedance, Z, was taken as the average of the impedance moduli from 4 to 12 Hz." The modulus of the reflection coefficient was taken as RC=(ZrZ)/(Zn+Z), as described by Westerhof et al. l4 Total aortic input pressure power (Pt) was computed as the summed product of instantaneous aortic pressure and flow
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Hormone analysis Plasma concentrations o f renin (normal values: -2.5 ng AIm-'.h-', atrial natriuretic factor (normal values: -80 pg.ml-l), and arginine vasopressin (normal values: -0.75 pg.rn1-l) were measured by radioimmunoassay; plasma noradrenaline [normal values: 250(50) pg.rn1-I1 was measured by high pressure liquid chromatogra hy and electrochemical detection as described previously.' 'I
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Statistics All reported data are presented as mean(SEM). Correlation coefficients were obtained by linear regression analysis (method of least squares).,, Statistical significance was accepted at the ~ ~ 0 . level.-+ 05
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over the cardiac cycle." Steady or mean aortic input pressure power (P,) is the product of mean aortic pressure and cardiac output. The difference, P,-P,, represents the oscillatory or pulsatile component of power, Po. Oscillatory power was also computed from impedance and flow moduli derived from Fourier analysis.16 There was an excellent correlation between these two independent methods of computation ( ~ 0 . 9 9 9 )Relative . oscillatory power was calculated as the ratio of P a , . The normal values of our laboratory were assessed in 12 control subjects [seven men, five women, mean age 55(SEM 6) years, range 45-70], who were undergoing cardiac catheterisation for various clinical indications, the most common being chest pain. No cardiovascular disease was found by haemodynamic measurements, left ventricular cineangiography, or coronary arteriography. None had a history of diabetes mellitus, severe hypercholesterolaemia, or arterial hypertension. Body weight and height were within the normal range. Their mean values are presented in table 11. The are inkxcellent accordance with those reported by )I I 5 17 18 others. Table I1 Normal values for left ventricular hydraulic load obtained in 12 control subjects without overt cardiovascular disease. Variable
Mean (SEM) Range
Characteristic impedance Z, (dynewm") Resistive term (dyne.s.cm") Zero crossing of impedance phase (Hz) Total aortic input pressure power (mW) Mean aortic input pressure power (mW) Oscillatory aortic input pressure power (mW) Relative oscillatory power (%)
76(8) 1324(155) 4.3(0.5) 1522(120) 1340(76) 182(12) 12(3)
52 - 105 895 - 1555 3.2 - 4.9 1024 - 2040 725 - 1867 6 0 - 178 7 - 18
The haemodynamic and hormonal data of 20 patients with mild to moderate chronic congestive heart failure are presented in table 111. There were minor differences for the mean values of several variables comparing patients with dilated cardiomyopathy and coronary artery disease: however, they did not reach statistical significance. The patients had moderately increased left ventricular volumes, a reduced left ventricular ejection fraction and cardiac output, and raised left ventricular filling pressure. Total peripheral resistance was increased, as was the resistive term. However, characteristic impedance and oscillatory power did not differ from the control values of our laboratory and those reported by others. With respect to the age dependency of characteristic impedance that was observed in 45 control subjects by Nichols and coworkers," in our heart failure patients, mean age 58(6) years, the mean measured value very closely approximated the mean calculated value of characteristic impedance, ie, 80(6) versus 82(3) d y n e . s ~ m - ~ . There was no interrelationship between characteristic impedance and total peripheral resistance (fig 4). Plasma concentrations of noradrenaline, renin, atrial natriuretic factor, and - to a smaller extent - arginine vasopressin showed moderate but significant elevations, indicating neurohormonal activation. Table III Haemod.vnamic and neurohortnonal characteristics of 20 patients with mild to moderate chronic congestive heart failure. Vuriable
Mean (SEM)
Systolic aortic pressure (mm Hg) 127(5) Diastolic aortic pressure (mm Hg) 720) Systolic pulmonary artery pressure (mm Hg) 48(5) Diastolic pulmonary artery pressure (mm Hg) 22(3) Pulmonary capillary wedge pressure (mm Hg) 21(2) Mean right atrial pressure (mm Hg) 9(1) Heart rate (beats,min-') W3) LV end diastolic volume index ( m l M 2 ) 160(13) 103( 13) LV end systolic volume index (ml.m-2) LV ejection fraction (%) 38(4) Cardiac index (litre.minm-*) 2.2(0.2) Total peripheral resistance (dynewm?) 1710(119) Characteristic impedance Z, (dyne.s.cm") 80(6) Resistive term (dynewxr?) 1969(155) Zero crossing of impedance phase (Hz) 4.6(0.5) 0.40(0.1) Complex reflection coefficientll-cz 966(83) Total aortic input pressure power (mW) Mean aortic input pressure power (mW) 867(74) Oscillatory aortic input pressure power (mW) 99(15) Relative oscillatory power (%) 10(1) Noradrenaline (pg,ml-') 462(62) Plasma renin concentration (ng AIm".h") 12(4) Atrial natriuretic peptide (pg.rn1-l) 408(64) Arginine vasopressin ( p g m - ' ) I . l(0.3)
Runge 98 - 157
53 - 96 24 - 82 8 - 39 7 - 39 1 - 18 63 - 107 81 - 222 32 - 178 16 - 68 1.1 - 3.3 826 - 2566 34 - 172 1041 - 3477 3.6 - 7.9 0.32 - 0.58 463 - 1740 425 - 1567 I8 - 278 5-21 132 - 1074 0.9 - 64 70 - 1030 0.3 - 4.0
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There was an excellent positive correlation between mean right atrial pressure and plasma atrial natriuretic factor. Noradrenaline concentrations showed a significant inverse correlation with cardiac output, and plasma renin concentration was negatively correlated with total peripheral resistance (fig 5). Plasma concentrations of arginine vasopressin, which were only slightly increased, showed borderline interrelationships with cardiac output and total peripheral resistance (table IV). Characteristic impedance, reflecting aortic distensibility, and relative oscillatory aortic input pressure power showed no close correlation with plasma concentrations of atrial natriuretic factor, arginine vasopressin, noradrenaline, and renin (figs 6 and 7). Other variables characterising the complex pressure-flow interrelationship, such as complex reflection coefficient and zero crossing of impedance phase, were not related to neurohormonal activation, the closest r value being 20.3. If these correlations were calculated for subgroups of patients with coronary artery disease or idiopathic dilated cardiomyopathy, the r values obtained showed no significant differences either between the two subgroups or with the total study population. Total aortic input pressure power or external ventricular power, closely reflecting left ventricular external work, showed excellent inverse correlations with plasma atrial natriuretic factors, noradrenaline, and renin concentration (fig 8), and there was a weak correlation with arginine vasopressin (r=-0.34; p=0.08).
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Table IV Correlations between neurohormonal and haemodynamic variables in 20 patients with mild to moderate chronic congestive heart fuilure. CO Noradrenaline Atrial natriuretic factor
PCW
RAP
r=+0.52 p=O.OI r=+0.88 r=0.001 r=4.41 r=+0.19 r=+0.36 p=O.O45 p=0.2 p=0.07
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r=+0.76 r=+O. 1 p=0.001 ~ ~ 0 . 4 r=+0.55 r=-0.63 p=0.006 p=O.O08
r=+0.47 p=0.03 Plasma renin concentration r = 4 . 6 0 r=+0.27 r=+0.45 r=+0.59 p=0.002 p=O. I2 ~ 4 . 0 2 p=0.003
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CO=cardiac oulput: PCW=pulnionary capillary wedge pressure; RAP=mean right atrial pressure; TPR=total peripheral resistance; EF=ejection fraction.
Figure 5 Scatterplots showing correlations between plasma concentratianv of atriul natriuretic factor (ANF) and right atrial
pressure (top; r=+0.88, p=O.O01), plrisma nciradrenaline concentration und cardiac output (middle; r = 4 6 4 . p=O.OOI )- rind plasma renin concentration (PRC) cind total peripheral resistance (bottom; r=-O.SY, p=0.003) in 20 patients with mild to tnoderute chronic congestive heart ,fniIure.
Discussion “Afterload”, which may be defined as the external factors that oppose the shortening of cardiac muscle fibres, is an important determinant of myocardial performance in the intact and particularly in the failing heart.:’ The pressure
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generated by the ventricle acts to distend the compliant aorta as well as to move blood forward. Measurement of “mean afterload’ allows no complete description of afterload, because it omits all information about time and frequency dependence. Mean ejection pressure, for example, provides no way of distinguishing between resistive and capacitative changes. The time varying pressure and the stress in the ventricular wall can be measured, but they are results of the afterload and cannot in any useful sense be said to be equul to afterload. Therefore, a complete assessment of afterload should take into account all of the external factors that oppose the ventricular ejection of blood. By definition, the arterial input impedance meets this requirement.’s ” By appropriate mathematical techniques, vascular impedance expressing pulsatile flow relationship - may be calculated as a spectrum of moduli and phases versus frequency” (fig 3). The impedance spectrum depends on two factors: (1) the physical properties of the artery, ie, viscoelasticity, dimension, etc, determine characteristic impedance Z,; (2) The reflected pressure and flow waves generated in more distal parts of the arterial tree produce frequency dependent oscillations around the input impedance Z,. The crucial role of the pulsatile component of left ventricular afterload expressed as characteristic impedance - may be delineated from a recent study done by Morita and coworker^.'^ They selectively increased the pulsatile afterload by bypassing the
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Figure 7 Sccitterplots showitig no close correlations between plasnici concentrcitioiis of noreidreiialiiie (top: r=@01, N S ) cind renin (PRC, bottom: r=-O. 1.5. N S ) cincl c~hurcicteristicinipedrince Z, in 20 peltierits with mild tn inoderiite chronic congestive hecirt jirilirre.
ascending to abdominal aorta with a non-compliant prosthesis. Mean arterial pressure, cardiac output, and systemic peripheral resistance remain unchanged, while characteristic impedance increased threefold. After three months significant left ventricular hypertrophy had developed, emphasising the role of pulsatile load and the need for its assessment. The physical properties of the arterial tree are major determinants of Characteristic impedance. In congestive heart failure they may be altered due to neurohormonal activation by different mechanisms. ( 1 ) Angiotensin 11, arginine vasopressin, and noradrenaline, the plasma concentrations of which are increased in congestive heart failure, might induce hypertrophy of aortic smooth muscle cells, as has been shown in vitro.h-yzx-3” (2) The arterial wall sodium content may be increased due to neurohormonal activation, as has been demonstrated in experimental congestive heart failure.“’ As a result of both mechanisms, the distensibility of the arterial tree could be reduced, thereby increasing the pulsatile load. (3) In contrast, atrial natriuretic factor, which is increased in the plasma in congestive heart failure,’” 3 1 might directly dilate the aorta, thereby increasing distensibility and reducing pulsatile load.’’ Our patients with chronic mild to moderate congestive heart failure showed no increase in characteristic impedance or relative oscillatory aortic input pressure power. This is in
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Figure 8 Scatterplots showing close negative correlations between plasma concentrations of atrial natriuretic factor (ANF; top; r=-0.64, p=O.OOl), noradrenaline (middle; r = 4 4 9 , p=0.015), and renin (PRC, bottom; r = 4 5 8 , p=O.o04) and total aortic input pressure power in 20 patients with mild to moderate chronic congestive heart failure.
accordance with data published by others.” 32 It is well known that characteristic impedance increases with age; however, age range in our patients was close enough to exclude significant age related effects.” Total peripheral resistance, usually accepted as a close reflection of left ventricular afterload, showed no interrelationship with characteristic impedance, indicating that the amount of pulsatile load cannot be delineated from mean haemodynamic data.
Neurohormonal activation, indicated by an increase in plasma concentrations of noradrenaline, renin, arginine vasopressin, and atrial natriuretic factor, showed good correlations with haemodynamic variables, ie, mean right atrial pressure, cardiac output and systemic vascular resistance. Total aortic input pressure power or external ventricular power as the sum of mean power - associated with mean flow - and pulsatile power - associated with vascular pulsations - closely reflects external heart work. Our patients with congestive heart failure showed decreased values of total aortic input pressure power, as has been reported by others.” There was a significant negative correlation between external ventricular power and each of the neurohormonal systems investigated. These findings confirm that neurohormonal mechanisms are activated in proportion to left ventricular dysfunction.33 The regression analyses of characteristic impedance and relative oscillatory power on neurohormonal systems showed no significant correlation. Because other interrelations investigated in our carefully performed study were quite close, the independency of pulsatile load from the degree of neurohumoral activation may not be due to the sample size of 20 patients with mild to moderate congestive heart failure. There are several possible explanations. (1) The above mentioned effects of neurohormonal activation on aortic distensibility play no important role in humans with mild to moderate congestive heart failure. The physical properties of the arterial system primarily reflect age and/or the degree of atherosclerosis.” This hypothesis is supported by a recently published study in which we found no acute effects of increasing plasma levels of endogenous atrial natriuretic factor on characteristic impedance in patients with congestive heart failure.” (2) In mild to moderate congestive heart failure the effects of the activated sympathethic nervous system and renin-angiotensin system, and probably raised plasma levels of arginine vasopressin (resulting in a decrease in arterial distensibility), would be counterbalanced by increased levels of atrial natriuretic factor, which might increase arterial di~tensibility.~~ ” The potential effects of angiotensin 11, arginine vasopressin, and noradrenaline on vascular smooth muscle cell hypertrophy and arterial wall sodium content might alter arterial distensibility only in advanced heart failure, when the influence of the sympathetic nervous system and the renin-angiotensin system overcomes effects of atrial natriuretic factor, and when considerable increases in plasma arginine vasopressin may be found.” 36 Under these circumstances, alterations in the physical properties of the arterial system secondary to neurohormonal activation could further increase pulsatile load. Whether data of Pepine et al, who found increased characteristic impedance in patients with more severe heart fail~re,~’ support this hypothesis remains to be clarified. Limitations
The present study used plasma levels as indices of neurohormonal activation in patients with chronic congestive heart failure. They are only estimates of hormonal activity at the receptor level and do not take into account possible alterations by receptor andor postreceptor regulation. 38 39 Moreover, recent data indicate that local autocrine and paracrine effects of neurohormonal systems might play a pivotal role in vascular tone and particularly in However, at the present time there is no possiblity of assessing their activity in vivo. Previous studies which investigated myocardial noradrenaline content to assess local sympathetic activity in patients with chronic congestive heart
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failure reported conflicting results." However, numerous large studies have shown that plasma levels reliably reflect overall activity of neurohormonal systems, particularily with respect to survival, the most important endpoint.' " A second limitation might be the fact that we investigated 20 heart failure patients along with 12 control subjects, using a method where day to day variability has not yet been studied in humans. Therefore small differences might go undetected. However, the observed ranges of characteristic impedance and relative oscillatory power in both groups were very similar, indicating that there is no relevant increase in early heart failure. Conclusion Our patients with mild to moderate chronic congestive heart failure showed neurohormonal activation. The pulsatile components of left ventricular afterload, however, were not increased and showed no interrelation with the degree of neurohormonal activation. This indicates that in the initial stages of congestive heart failure there is no secondary increase in left ventricular pulsatile load, as a result of trophic effects of neurohormonal systems, which might be deleterious to the failing heart. Received 12 August 1991, accepted 14 October 1991 Key terms: aortic input impedance; pulsatile left ventricular load; hydraulic power; congestive heart failure; neurohormonal activation
14 Westerhof N, Sipkema P, Vanden Bos BG, Elzinga G. Forward and
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backward waves in the arterial system. Cardiovasc Res 1972; 6:648-56. Nichols WW, Conti CR, Walker WE, Milnor WR. Input impedance of the systemic circulation in man. Circ Res 1977;40:451-8. Milnor WR, Bergel DH. Bargainer JD. Hydraulic power associated with pulmonary blood flow and its relation to heart rate. Circ Res 1966;19:467-80. Nichols WW, O'Rourke MF, Avolio AP, et a/ Effects of age on ventricular-vascular coupling. Am J Cardiol 1985;55:1179-84. Nichols WW, O'Rourke MF, Avolio AP, Yaginuma T, Pepine CJ, Conti R. Ventricular-vascular interaction in patients with mild systemic hypertension and normal peripheral resistance. Circulation 1986;74:455-62. Riegger AJG, Liebau G, Kochsiek K. Antidiuretic hormone in congestive heart failure. Am J Med 1982;72:49-52. Riegger AJG, Kromer EP, Kochsiek K. Human atrial natriuretic peptide: plasma levels, hemodynamic, hormonal and renal effects in patients with severe congestive heart failure. J Cardiovasc Pharmucol 1986;8:1107-12. Kromer EP, Elsner D, Kahles HW, Riegger AJG. Effects of atriopeptidase inhibitor UK 79300 on left ventricular hydraulic load in patients with congestive heart failure. Am J Hypertens 199 1;4:46&3. Wallenstein S, Zucker CL, Fleiss JL. Some statistical methods useful in circulation research. Circ Res I980;47: 1-9. Ross J J, Covell JW, Sonnenblick EH, Braunwald E. Contractile state of the heart characterized by force-velocity relationship in variable afterload and isovolumic beats. Circ Res 1966;18: 149-63. Milnor WR. Arterial imoedance as ventricular afterload.Circ Res 1975;36:565-70. Wetterer E. Die Wirkune der Herztatiekeit auf die Dvnamik des Arteriensystems. Verh -Drsch Ges kreislauf-forscx 1956;22: 26-60. McDonald DA, Taylor MG. Hydrodynamics of the arterial circulation. frog Biophys I959;9: 107-22. Morita S, Asou T, Kuboyama I, Tokunaga K, Harasawa Y, Sunagawa K. Increased characteristic impedance causes left ventricular hvoertroohv in does (abstract). Circulation 1989: 8O(suppl II):Ai99. Geisterfer AAT. Peach MJ. Owens GK. Aneiotensin I1 induces hypertrophy, not hyperplasia, of cultured rat a h c smooth muscle cells. Circ Res 1988;62:749-56. Naftilan AJ, Pratt RE, Dzau VJ. Induction of platelet-derived growth factor a-chain and c-myc gene expressions by angiotensin I1 in cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1419-23. Berk BC. Vekshtein V. Gordon HM. Tsuda T. Aneiotensin IIstimulated protein synthesis in cultured vascular smioth muscle cell. Hypertension 1989;13:305-14. Tikkanen I, Fyhrquist IR, Metsirinne K, Leidenius R. Plasma atrial natriuretic peptide in cardiac disease and during infusions in healthy volunteers. Lancet 1985;ii:66-9. Merillon JP, Fontenier G, Lerallut JF, et al. Aortic input impedance in heart failure: comparison with normal subjects and its changes during vasodilator therapy. Eur Heart J I984;5:447-55. Riegger AJG. The role of atrial natriuretic factor in congestive heart failure. frog Pharmacol Clin Pharmacol 1990;7: 101-15. Holmer SR, Riegger AJG, Nothesis W, Kromer EP, Kochsiek K. Hemodynamic changes and renal plasma flow in early heart failure: Implications for renin, aldosterone, norepinephrine, atrial natriuretic peptide and prostacyclin. Basic Res Cardiol 1987; 82: 101-8. Holtz J, Sommer 0, Bassenge E. Inhibition of sympath+adrenal activity by atrial natriuretic peptide in the dog. Hypertension 1987;9:350-4. Riegger AJG. Vasopressin in heah failure. In: Jakob R, Seipel L, Zucker IH eds. Cardiac dilutation. Stuttgart: Gustav Fisher, 1990: 156-63. Pepine CJ, Nicholls WW, Conti CR. Aortic input impedance in heart failure. Circulation 1977;58:460-5. Bohm M, Gierschik P, Jakobs KH, et al. Increase of G,, in human hearts with dilated but not ischemic cardiomvouathv. Circulation 1990;82:1249-65. Holmer SR. Homcv CJ. G-Proteins in the heart: a redundant and diverse transmembrane signalling network. Circulation 1991;84:1892-902. Dzau VJ, Gibbons GH. Autocrine-paracrine mechanisms of vascular myocytes in systemic hypertension. Am J Cardiol 1987; 60599-1 03. Kawai C, Yui Y, Hoshino T, Sasayama S , Matsumori A. Mvocardial catecholamines in hvuertrouhic and dilated (congestive) cardiomyopathy: a biopsy *study: J Am Coll Cardiol 1983;2:83440. L
28 1 Riegger AJG, Liebau G, Holzschuh M, Witkowksi D, Steilner H,
2
3 4 5
6 7 8 9 10
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Kochsiek K. Role or the renin-angiotensin system in the development of congestive heart failure in the dog as assessed by chronic converting-enzyme blockade. Am J Curdiol 1984;53: 614-8. Francis GS, Bendict C, Johnstone DE, et a/. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. Circularion 1990382:1724-9. Cohn JN, Levine TB, Olivari MT, et a/. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;331:819-23. Gottlieb SS, Kukin ML, Ahern D, Packer M. Prognostic importance of atrial natriuretic peptide in patients with chronic heart failure. J Am Coll Cardiol 1989;13:1534-9. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation 1990;82:1730-6. Blaes N, Boissel JP. Growth-stimulating effect of catecholamines on rat aortic smooth muscle cells in culture. J Cell Physiol 1983; 116: 167-72. Campbell-Boswell M, Robertson AL. Effects of angiotensin I1 and vasopressin on human smooth muscle cells in vitro. Exp Mol Pathol 198 1;35:266-76. Bevan RD. Trophic effects of peripheral adrenergic nerves on vascular structure. Hyperrension 1984;6(suppl 3):19-26. Geisterfer AAT, Owens GK. Arginine vasopressin-induced hypertrophy of cultured rat aortic smooth muscle cells. Hypertension 1989;14:413-20. Zelis R, Delea CS, Coleman HN, Mason DT. Arterial sodium content in experiment congestive heart failure. Circulation 1970;41:213-20. Laskey WK, Kussmaul WG, Martin JL, Kleaveland JP, Hirshfeld JW,Shroff S . Characteristics of vascular hydraulic load in patients with heart failure. Circularion 1985;72:61-71. Hirooka Y, Takeshita A, Imaizumi T, Nakamura N, Tomoike H, Nakamura M. Effects of a-human atrial natriuretic peptide on the interrelationship of aterial pressure, aortic nerve activity and aortic diameter. Circ Res 1988;63:987-96. Dodge HT, Sandler H, Ballew DW, Lord JD.The use of biplane angiography for the measurement of left ventricular volume in man. Am Heart J 1960;60:762-9.
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42 Pierpont GL, Francis GS, DeMaster EG. et crl. Heterogeneous mvocardial catecholamine concentrations in patients with cchgestive heart failure. Am J Cnrdiol 1987;60:316-21.
43 Lee WH. Packer M. Prognostic importance of serum sodium concentration and its moditication by convertin!: e n 7 y m r inhibition in patients with severe congestive heart faiiure. Circirlntiorr I 986;76:2S7-67.
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Aortic input impedence and neurohormonal activation in patients with mild to moderate chronic congestive heart failure Eckhard P Kromer, Dietmar Elsner, Stephan R Holmer, Andreas Muntze, and Gunter A J Riegger Objective: The aim was to investigate the interrelation between pulsatile components (assessed by determination of aortic input impedance) and neurohormonal activation in chronic congestive heart failure. Methods: Aortic input impedance, plasma noradrenaline, renin, atrial natriuretic factor, and arginine vasopressin were measured in 20 patients with mild to moderate chronic congestive heart failure (coronary artery disease n=12, idiopathic dilated cardiomyopathy n=8). Results: Cardiac index [2.2(SEM 0.3) litre.min-'.m-'] and left ventricular ejection fraction [38(4)%] were reduced, and pulmonary wedge pressure was increased [2 l(2) mmHg]. Plasma concentrations of noradrenaline [462(62) p g m - l ] , renin [ 12(4) ng AI.ml.h-l], atrial natriuretic factor [408(64) p g d ] , and - to a slight degree - arginine vasopressin [ l.l(O.3) pg.ml-'] were increased. Characteristic impedance Z, [80(6) dyne.scrn-') and relative oscillatory aortic input pressure power [ 10(1 )%] - both reflecting the pulsatile components of left ventricular afterload - were within the normal range. There was no significant correlation between these variables and the degree of neurohormonal activation (r values: -0.05 to -0.35). Conclusions: The data show that in patients with mild to moderate chronic congestive heart failure there is no interrelationship between the degree of neurohormonal activation and pulsatile components of left ventricular afterload. This may indicate that in these stages of heart failure there are no trophic effects of stimulated neurohormonal systems on the physical properties of the great arteries.
C
ongestive heart failure is characterised by a primary abnormality in systolic and/or diastolic function of the heart. Secondarily a number of neurohormonal mechanisms are activated in order to preserve circulatory homeostasis, ie, to support systemic blood pressure, cardiac contractility, and glomerular filtration rate (table I). Neurohormonal activation, which may be found even in early congestive heart failure,' ' was originally viewed as a beneficial compensatory response. However, an abundant endogenous release of vasoconstrictor hormones may exert deleterious haemodynamic effects. The increase of left ventricular preload and afterload may accelerate progression of heart failure. The degree of neurohormonal activation reflects the severity of the heart failure, and may be a prognostic factor in such patients.'-' In addition to effects on vascular tone, noradrenaline, angiotensin 11, and arginine vasopressin may exert direct trophic effects on vascular smooth muscle cells in vitro.6-9 Furthermore, arterial wall sodium content may increase due to neurohormonal activation.'" Thus at least three different mechanisms might contribute to the increase in the loading conditions of the failing heart. However, it is difficult exactly to assess left ventricular afterload, which plays a crucial role in left ventricular function in congestive heart failure. Usually mean left ventricular ejection pressure or systemic vascular resistance are accepted as close reflections. Systemic vascular resistance represents the resistance to steady flow and as such is one component of afterload. It does not take
into account the pulsatile component of arterial hydraulic load. Aortic input impedance represents the vascular hydraulic load encountered by the ejecting left ventricle." Recent data from Hirooka et (11, obtained in an animal study, suggest that atrial natriuretic factor may directly dilate the aorta," thereby reducing the pulsatile component of left venticular afterload. This could be beneficial to the impaired left ventricle of patients with congestive heart failure. Thus neurohormonal activation may exert complex effects on steady and pulsatile components of left ventricular afterload. Steady components of left ventricular afterload usually show fair correlations with the degree of neurohormonal activation. The interrelation with pulsatile components, however, has not yet been investigated. In the present study we investigated neurohormonal activation and variables characterising left ventricular hydraulic load in patients with chronic mild to moderate congestive heart failure.
Methods Patietit population
We studied 20 patients (1 2 men, eight women, mean age 58 (SEM 3) years, range 52 to 68) with stable mild to moderate chronic congestive heart failure. Patients with a history of diabetes mellitus and/or arterial hypertension were excluded. The diagnosis of congestive heart failure was established using the patients' carefully obtained history along with
I1 Medizinische Klinik, Universitatsklinikum Regensburg, Franz-Joseph-StrauS-Allee 1 1, 8400 Regensburg, Germany: E P Kromer, D Elsner, S R Holmer, A Muntze, G A J Riegger. Correspondence to Professor Kromer.
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Table I Neurohormonal svstems activated in patients with chronic congestive heart failure. Vasoconstriction:
Vasodilatation:
Sympathetic nervous system Renin-angiotensin-aldosterone system Arginine vasopressin Endothelin- I Atrial natriuretic factor Prostaglandin IZ Prostaglandin EZ Endothelium derived relaxing factor Bradykinin Dopamine Vasoactive intestinal peptide
chest x ray examinations and echocardiographic and cardiac catheterisation data. The cause of congestive heart failure was coronary artery disease (n= 12) and idiopathic dilated cardiomyopathy (n=8). All patients had sinus rhythm, and none had significant mitral regurgitation or peripheral oedema. The mean duration of congestive heart failure was 3.7 years (range 1.2-6.3). Serum sodium concentration, total protein content, and packed cell volume were within the normal range in each patient. Written, informed consent was obtained from all patients before the study. The study protocol was approved by the ethics committee of the University of Wiirzburg. Study protocol
Except for digitalis all medication was discontinued 3 d prior to the study. On the day of the investigation digitalis was also withheld. The patients were in a fasting condition for 12 h. All investigations were performed between 9.00 and 10.00 hours to avoid confounding diurnal effects. Under local anaesthesia the right femoral vein and artery were cannulated. After a period of 1 h, blood was drawn from the pulmonary artery for determination of plasma noradrenaline, renin, arginine vasopressin and atrial natriuretic factor. Right heart catheterisation was performed using a 7 F Swan-Ganz balloon flotation catheter. Cardiac output was measured by thermodilution in triplicate. A Millar microtip catheter (SVPC-684-A, Millar, Houston, TX, USA), containing a velocity probe close to a pressure sensor, was advanced to the bulbus aortae. The velocity probe was energised by an 800 Hz square wave electromagnetic flow meter (Servomed, Hellige, Freiburg, Germany), and velocity signals were recorded at a 30 Hz filter setting. After repeated measurements of pressure and velocity, left ventriculograms were obtained in a right anterior oblique projection, and left ventricular ejection fraction was calculated from the left ventricular v01umes.'~
Data analysis Pressure and velocity signals were digitised along with the ECG, using a 12 bit analogue to digital converter (Data Translation 2814, Marlborough, MA, USA) at a sampling rate of 400 Hz. The data were stored on an IBM compatible personal computer. For ECG triggered signal averaging, 10 to 30 beats with optimal velocity configuration were superimposed (figs 1 and 2). No postectopic beats were included and only beats with RR intervals within 5% of the mean value were analysed. The averaged velocity signal was scaled to volumetric flow by setting the integrated area beneath the velocity signal equal to the simultaneously determined cardiac output. Thereafter the pressure and flow signals were subjected to fast Fourier transformation (15 harmonics). The respective pressure (Pn) and flow (Qn) moduli for each harmonic were used to derive the impedance modulus (Zn) as Pn/Qn, while impedance phase is the
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Figure I I7 non-consecutive beats from a patient with rnoderiitr chronic congestive heart failure superimposed io examine belit to beat variability in pressure (top) and velocity (bottom).
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Figure 2 Computer processed, signal averaged composite pressure (top) and velocity (bottom) waves derived from the 17 beats shown in jig 1.
difference of pressure and flow phase. The aortic input impedance spectrum was displayed as a plot of impedance modulus v frequency (fig 3). The 0 Hz or resistive term of the impedance spectrum corresponds to the systemic vascular resistance. Characteristic impedance, Z, was taken as the average of the impedance moduli from 4 to 12 Hz." The modulus of the reflection coefficient was taken as RC=(ZrZ)/(Zn+Z), as described by Westerhof et al. l4 Total aortic input pressure power (Pt) was computed as the summed product of instantaneous aortic pressure and flow
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Hormone analysis Plasma concentrations o f renin (normal values: -2.5 ng AIm-'.h-', atrial natriuretic factor (normal values: -80 pg.ml-l), and arginine vasopressin (normal values: -0.75 pg.rn1-l) were measured by radioimmunoassay; plasma noradrenaline [normal values: 250(50) pg.rn1-I1 was measured by high pressure liquid chromatogra hy and electrochemical detection as described previously.' 'I
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Statistics All reported data are presented as mean(SEM). Correlation coefficients were obtained by linear regression analysis (method of least squares).,, Statistical significance was accepted at the ~ ~ 0 . level.-+ 05
Results 0
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over the cardiac cycle." Steady or mean aortic input pressure power (P,) is the product of mean aortic pressure and cardiac output. The difference, P,-P,, represents the oscillatory or pulsatile component of power, Po. Oscillatory power was also computed from impedance and flow moduli derived from Fourier analysis.16 There was an excellent correlation between these two independent methods of computation ( ~ 0 . 9 9 9 )Relative . oscillatory power was calculated as the ratio of P a , . The normal values of our laboratory were assessed in 12 control subjects [seven men, five women, mean age 55(SEM 6) years, range 45-70], who were undergoing cardiac catheterisation for various clinical indications, the most common being chest pain. No cardiovascular disease was found by haemodynamic measurements, left ventricular cineangiography, or coronary arteriography. None had a history of diabetes mellitus, severe hypercholesterolaemia, or arterial hypertension. Body weight and height were within the normal range. Their mean values are presented in table 11. The are inkxcellent accordance with those reported by )I I 5 17 18 others. Table I1 Normal values for left ventricular hydraulic load obtained in 12 control subjects without overt cardiovascular disease. Variable
Mean (SEM) Range
Characteristic impedance Z, (dynewm") Resistive term (dyne.s.cm") Zero crossing of impedance phase (Hz) Total aortic input pressure power (mW) Mean aortic input pressure power (mW) Oscillatory aortic input pressure power (mW) Relative oscillatory power (%)
76(8) 1324(155) 4.3(0.5) 1522(120) 1340(76) 182(12) 12(3)
52 - 105 895 - 1555 3.2 - 4.9 1024 - 2040 725 - 1867 6 0 - 178 7 - 18
The haemodynamic and hormonal data of 20 patients with mild to moderate chronic congestive heart failure are presented in table 111. There were minor differences for the mean values of several variables comparing patients with dilated cardiomyopathy and coronary artery disease: however, they did not reach statistical significance. The patients had moderately increased left ventricular volumes, a reduced left ventricular ejection fraction and cardiac output, and raised left ventricular filling pressure. Total peripheral resistance was increased, as was the resistive term. However, characteristic impedance and oscillatory power did not differ from the control values of our laboratory and those reported by others. With respect to the age dependency of characteristic impedance that was observed in 45 control subjects by Nichols and coworkers," in our heart failure patients, mean age 58(6) years, the mean measured value very closely approximated the mean calculated value of characteristic impedance, ie, 80(6) versus 82(3) d y n e . s ~ m - ~ . There was no interrelationship between characteristic impedance and total peripheral resistance (fig 4). Plasma concentrations of noradrenaline, renin, atrial natriuretic factor, and - to a smaller extent - arginine vasopressin showed moderate but significant elevations, indicating neurohormonal activation. Table III Haemod.vnamic and neurohortnonal characteristics of 20 patients with mild to moderate chronic congestive heart failure. Vuriable
Mean (SEM)
Systolic aortic pressure (mm Hg) 127(5) Diastolic aortic pressure (mm Hg) 720) Systolic pulmonary artery pressure (mm Hg) 48(5) Diastolic pulmonary artery pressure (mm Hg) 22(3) Pulmonary capillary wedge pressure (mm Hg) 21(2) Mean right atrial pressure (mm Hg) 9(1) Heart rate (beats,min-') W3) LV end diastolic volume index ( m l M 2 ) 160(13) 103( 13) LV end systolic volume index (ml.m-2) LV ejection fraction (%) 38(4) Cardiac index (litre.minm-*) 2.2(0.2) Total peripheral resistance (dynewm?) 1710(119) Characteristic impedance Z, (dyne.s.cm") 80(6) Resistive term (dynewxr?) 1969(155) Zero crossing of impedance phase (Hz) 4.6(0.5) 0.40(0.1) Complex reflection coefficientll-cz 966(83) Total aortic input pressure power (mW) Mean aortic input pressure power (mW) 867(74) Oscillatory aortic input pressure power (mW) 99(15) Relative oscillatory power (%) 10(1) Noradrenaline (pg,ml-') 462(62) Plasma renin concentration (ng AIm".h") 12(4) Atrial natriuretic peptide (pg.rn1-l) 408(64) Arginine vasopressin ( p g m - ' ) I . l(0.3)
Runge 98 - 157
53 - 96 24 - 82 8 - 39 7 - 39 1 - 18 63 - 107 81 - 222 32 - 178 16 - 68 1.1 - 3.3 826 - 2566 34 - 172 1041 - 3477 3.6 - 7.9 0.32 - 0.58 463 - 1740 425 - 1567 I8 - 278 5-21 132 - 1074 0.9 - 64 70 - 1030 0.3 - 4.0
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There was an excellent positive correlation between mean right atrial pressure and plasma atrial natriuretic factor. Noradrenaline concentrations showed a significant inverse correlation with cardiac output, and plasma renin concentration was negatively correlated with total peripheral resistance (fig 5). Plasma concentrations of arginine vasopressin, which were only slightly increased, showed borderline interrelationships with cardiac output and total peripheral resistance (table IV). Characteristic impedance, reflecting aortic distensibility, and relative oscillatory aortic input pressure power showed no close correlation with plasma concentrations of atrial natriuretic factor, arginine vasopressin, noradrenaline, and renin (figs 6 and 7). Other variables characterising the complex pressure-flow interrelationship, such as complex reflection coefficient and zero crossing of impedance phase, were not related to neurohormonal activation, the closest r value being 20.3. If these correlations were calculated for subgroups of patients with coronary artery disease or idiopathic dilated cardiomyopathy, the r values obtained showed no significant differences either between the two subgroups or with the total study population. Total aortic input pressure power or external ventricular power, closely reflecting left ventricular external work, showed excellent inverse correlations with plasma atrial natriuretic factors, noradrenaline, and renin concentration (fig 8), and there was a weak correlation with arginine vasopressin (r=-0.34; p=0.08).
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Table IV Correlations between neurohormonal and haemodynamic variables in 20 patients with mild to moderate chronic congestive heart fuilure. CO Noradrenaline Atrial natriuretic factor
PCW
RAP
r=+0.52 p=O.OI r=+0.88 r=0.001 r=4.41 r=+0.19 r=+0.36 p=O.O45 p=0.2 p=0.07
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r=+0.76 r=+O. 1 p=0.001 ~ ~ 0 . 4 r=+0.55 r=-0.63 p=0.006 p=O.O08
r=+0.47 p=0.03 Plasma renin concentration r = 4 . 6 0 r=+0.27 r=+0.45 r=+0.59 p=0.002 p=O. I2 ~ 4 . 0 2 p=0.003
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CO=cardiac oulput: PCW=pulnionary capillary wedge pressure; RAP=mean right atrial pressure; TPR=total peripheral resistance; EF=ejection fraction.
Figure 5 Scatterplots showing correlations between plasma concentratianv of atriul natriuretic factor (ANF) and right atrial
pressure (top; r=+0.88, p=O.O01), plrisma nciradrenaline concentration und cardiac output (middle; r = 4 6 4 . p=O.OOI )- rind plasma renin concentration (PRC) cind total peripheral resistance (bottom; r=-O.SY, p=0.003) in 20 patients with mild to tnoderute chronic congestive heart ,fniIure.
Discussion “Afterload”, which may be defined as the external factors that oppose the shortening of cardiac muscle fibres, is an important determinant of myocardial performance in the intact and particularly in the failing heart.:’ The pressure
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generated by the ventricle acts to distend the compliant aorta as well as to move blood forward. Measurement of “mean afterload’ allows no complete description of afterload, because it omits all information about time and frequency dependence. Mean ejection pressure, for example, provides no way of distinguishing between resistive and capacitative changes. The time varying pressure and the stress in the ventricular wall can be measured, but they are results of the afterload and cannot in any useful sense be said to be equul to afterload. Therefore, a complete assessment of afterload should take into account all of the external factors that oppose the ventricular ejection of blood. By definition, the arterial input impedance meets this requirement.’s ” By appropriate mathematical techniques, vascular impedance expressing pulsatile flow relationship - may be calculated as a spectrum of moduli and phases versus frequency” (fig 3). The impedance spectrum depends on two factors: (1) the physical properties of the artery, ie, viscoelasticity, dimension, etc, determine characteristic impedance Z,; (2) The reflected pressure and flow waves generated in more distal parts of the arterial tree produce frequency dependent oscillations around the input impedance Z,. The crucial role of the pulsatile component of left ventricular afterload expressed as characteristic impedance - may be delineated from a recent study done by Morita and coworker^.'^ They selectively increased the pulsatile afterload by bypassing the
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Figure 7 Sccitterplots showitig no close correlations between plasnici concentrcitioiis of noreidreiialiiie (top: r=@01, N S ) cind renin (PRC, bottom: r=-O. 1.5. N S ) cincl c~hurcicteristicinipedrince Z, in 20 peltierits with mild tn inoderiite chronic congestive hecirt jirilirre.
ascending to abdominal aorta with a non-compliant prosthesis. Mean arterial pressure, cardiac output, and systemic peripheral resistance remain unchanged, while characteristic impedance increased threefold. After three months significant left ventricular hypertrophy had developed, emphasising the role of pulsatile load and the need for its assessment. The physical properties of the arterial tree are major determinants of Characteristic impedance. In congestive heart failure they may be altered due to neurohormonal activation by different mechanisms. ( 1 ) Angiotensin 11, arginine vasopressin, and noradrenaline, the plasma concentrations of which are increased in congestive heart failure, might induce hypertrophy of aortic smooth muscle cells, as has been shown in vitro.h-yzx-3” (2) The arterial wall sodium content may be increased due to neurohormonal activation, as has been demonstrated in experimental congestive heart failure.“’ As a result of both mechanisms, the distensibility of the arterial tree could be reduced, thereby increasing the pulsatile load. (3) In contrast, atrial natriuretic factor, which is increased in the plasma in congestive heart failure,’” 3 1 might directly dilate the aorta, thereby increasing distensibility and reducing pulsatile load.’’ Our patients with chronic mild to moderate congestive heart failure showed no increase in characteristic impedance or relative oscillatory aortic input pressure power. This is in
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Total aortic input pressure power (mW)
Figure 8 Scatterplots showing close negative correlations between plasma concentrations of atrial natriuretic factor (ANF; top; r=-0.64, p=O.OOl), noradrenaline (middle; r = 4 4 9 , p=0.015), and renin (PRC, bottom; r = 4 5 8 , p=O.o04) and total aortic input pressure power in 20 patients with mild to moderate chronic congestive heart failure.
accordance with data published by others.” 32 It is well known that characteristic impedance increases with age; however, age range in our patients was close enough to exclude significant age related effects.” Total peripheral resistance, usually accepted as a close reflection of left ventricular afterload, showed no interrelationship with characteristic impedance, indicating that the amount of pulsatile load cannot be delineated from mean haemodynamic data.
Neurohormonal activation, indicated by an increase in plasma concentrations of noradrenaline, renin, arginine vasopressin, and atrial natriuretic factor, showed good correlations with haemodynamic variables, ie, mean right atrial pressure, cardiac output and systemic vascular resistance. Total aortic input pressure power or external ventricular power as the sum of mean power - associated with mean flow - and pulsatile power - associated with vascular pulsations - closely reflects external heart work. Our patients with congestive heart failure showed decreased values of total aortic input pressure power, as has been reported by others.” There was a significant negative correlation between external ventricular power and each of the neurohormonal systems investigated. These findings confirm that neurohormonal mechanisms are activated in proportion to left ventricular dysfunction.33 The regression analyses of characteristic impedance and relative oscillatory power on neurohormonal systems showed no significant correlation. Because other interrelations investigated in our carefully performed study were quite close, the independency of pulsatile load from the degree of neurohumoral activation may not be due to the sample size of 20 patients with mild to moderate congestive heart failure. There are several possible explanations. (1) The above mentioned effects of neurohormonal activation on aortic distensibility play no important role in humans with mild to moderate congestive heart failure. The physical properties of the arterial system primarily reflect age and/or the degree of atherosclerosis.” This hypothesis is supported by a recently published study in which we found no acute effects of increasing plasma levels of endogenous atrial natriuretic factor on characteristic impedance in patients with congestive heart failure.” (2) In mild to moderate congestive heart failure the effects of the activated sympathethic nervous system and renin-angiotensin system, and probably raised plasma levels of arginine vasopressin (resulting in a decrease in arterial distensibility), would be counterbalanced by increased levels of atrial natriuretic factor, which might increase arterial di~tensibility.~~ ” The potential effects of angiotensin 11, arginine vasopressin, and noradrenaline on vascular smooth muscle cell hypertrophy and arterial wall sodium content might alter arterial distensibility only in advanced heart failure, when the influence of the sympathetic nervous system and the renin-angiotensin system overcomes effects of atrial natriuretic factor, and when considerable increases in plasma arginine vasopressin may be found.” 36 Under these circumstances, alterations in the physical properties of the arterial system secondary to neurohormonal activation could further increase pulsatile load. Whether data of Pepine et al, who found increased characteristic impedance in patients with more severe heart fail~re,~’ support this hypothesis remains to be clarified. Limitations
The present study used plasma levels as indices of neurohormonal activation in patients with chronic congestive heart failure. They are only estimates of hormonal activity at the receptor level and do not take into account possible alterations by receptor andor postreceptor regulation. 38 39 Moreover, recent data indicate that local autocrine and paracrine effects of neurohormonal systems might play a pivotal role in vascular tone and particularly in However, at the present time there is no possiblity of assessing their activity in vivo. Previous studies which investigated myocardial noradrenaline content to assess local sympathetic activity in patients with chronic congestive heart
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failure reported conflicting results." However, numerous large studies have shown that plasma levels reliably reflect overall activity of neurohormonal systems, particularily with respect to survival, the most important endpoint.' " A second limitation might be the fact that we investigated 20 heart failure patients along with 12 control subjects, using a method where day to day variability has not yet been studied in humans. Therefore small differences might go undetected. However, the observed ranges of characteristic impedance and relative oscillatory power in both groups were very similar, indicating that there is no relevant increase in early heart failure. Conclusion Our patients with mild to moderate chronic congestive heart failure showed neurohormonal activation. The pulsatile components of left ventricular afterload, however, were not increased and showed no interrelation with the degree of neurohormonal activation. This indicates that in the initial stages of congestive heart failure there is no secondary increase in left ventricular pulsatile load, as a result of trophic effects of neurohormonal systems, which might be deleterious to the failing heart. Received 12 August 1991, accepted 14 October 1991 Key terms: aortic input impedance; pulsatile left ventricular load; hydraulic power; congestive heart failure; neurohormonal activation
14 Westerhof N, Sipkema P, Vanden Bos BG, Elzinga G. Forward and
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