Volume overload heart failure: length-tension curves, and response to P-agonists, Ca2+, and glucagon WALTER H. NEWMAN Department of Pharmacology, Medical Charleston, South Carolina 29403

University

NEWMAN, WALTER H. Volume overload heart failure: length-tension curves, and response to P-agonists, Ca2+, and glucagon. Am. J. Physiol. 235(6): H690-H700, 1978 or Am. J. Physiol. : Heart Circ. Physiol. 4(6): H690-H700, 1978. - Left ventricular force-generating capacity was determined in 19 anesthetized dogs with heart failure (HF) from aortocaval fistula. At the time of study all dogs had ascites, edema, and elevated pulmonary wedge pressure. Length-contractile force (CF) curves recorded from the left ventricle (LV) with a modified Walton-Brodie arch indicated that the LV was operating on the ascending limb of the length-CF curve at 62.4 2 0.1% L,,, in the normal group and in the HF group at 83.4 t 2.7% Lax. In HF the length-CF curve was depressed when compared to normal and was further depressed when CF in grams was normalized for changes in LV wall thickness and expressed as g/cm”. Additionally, dose-response curves of CF in response to injected norepinephrine, isoproterenol, glucagon, and calcium were depressed when compared to the normal group while the response of heart rate and blood These findings indicate that pressure was not different. volume overload HF is associated with depressed ventricular muscle function and a depressed response to inotropic drugs. contractile

force; norepinephrine;

isoproterenol

STATE of hypertrophied cardiac muscle obtained from animal models of ventricular overload seems to depend on the nature and duration of the chronic increase in load imposed on the ventricle. Pressure-overload hypertrophy, generally produced by constriction of an outflow vessel, results in depression of maximal muscle shortening velocity (V,,,) and length-dependent tension development (6, 7, 20, 21, 23). On the other hand, hypertrophy resulting from volume overload appears not to be associated with a depression of these indices of the contractile state (5, 16, 26, 27). In pressure-overload models, when signs of congestive heart failure develop, there is further depression of the contractile state assessed as Vmax or length-dependent developed tension (23, 24). However, studies of cardiac muscle function in chronic volume overload-induced heart failure are in general lacking and, further, Taylor et al. (25) have reported that in a dog model of chronic volume overload which produced signs of heart failure (i.e., ascites, limb edema, pleural effusion and generalized circulatory congestion), left ventricular THE CONTRACTILE

H690

of South Carolina,

contractility, as judged by the tension-velocity relationship, remained normal. Therefore, the purpose of the present study was to determine the contribution of muscle length and mass-dependent mechanisms and alterations in the inotropic state of the myocardium to the force-generating capacity of the left ventricle in a model of chronic volume overload that produces the signs of heart failure. Further, since the sympathetic nervous system is thought to play a significant role in maintaining cardiac output in heart failure (13), the ability of the chronically volume overloaded left ventricle to respond to the P-agonists, norepinephrine and isoproterenol, was determined. To gain some insight into the responsiveness of the P-receptor in heart failure, dose-response curves for two positive inotropic agents that do not act through the P-receptor, glucagon and calcium, were also determined. METHODS

Chronic volume overload was induced in 14 mongrel dogs (wt 21-33 kg, mean 25.3 kg) by creating an infrarenal aortocaval fistula as described by Taylor et al. (25). Briefly, after anesthesia with 25 mg/kg pentobarbital, the abdominal aorta and vena cava were exposed and a side-to-side anastomosis, 15 mm in length, was constructed. The animals were returned to the kennels and studied after a period averaging 3.5 mo (range, 6 wk to 7 mo). At the time of study, all animals had elevated pulmonary wedge pressures (PWP), ascites, and limb edema. Data obtained from these dogs were compared to data obtained from 17 normal dogs and, to control for the altered hemodynamics caused by the fistula, to data from 6 dogs in which the fistula was created on the same day as the experiment. For the experimental proceSurgical preparation. dure, all animals were anesthetized with 25 mg/kg pentobarbital, placed on a Harvard respirator, and respired with 100% 0,. Throughout all procedures blood pH was monitored and kept between 7.35 and 7.45 by adjusting the respiratory rate. Prior to thoracotomy, PWP was measured with a no. 5F Swan-Ganz catheter introduced through the right jugular vein and connected to a Statham P23BC transducer. After this measurement, the catheter was withdrawn to a point just outside the right atrium and used for drug admin-

0363-6135/78/0000-0000$01.25

Copyright

0

1978 the

American

Physiological

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Society

HEART

FAILURE:

LENGTH-TENSION,

AND

AGONISTS,

CA'+,

istration. Bilateral vagotomy - was performed in the neck to prevent cardiac arrhythmias associated with the higher doses of norepinephrine. Systemic arterial pressure was recorded with a Statham P23db transducer connected to a catheter in the right carotid artery. Heart rate was recorded with a tachometer of our own design. A thoracptomy was performed through the left fifth intercostal space and the pericardium was opened and sutured to the chest wall. Length-tension curves. A modified Walton-Brodie strain-gauge arch was attached to the free wall of the left ventricle in an area free of papillary muscles and oriented nearly perpendicular to the interventricular sulcus. Modifications to the arch consisted of 1) a micrometer screw drive with which precise increments in the length of the subtended muscl .e segment I could be made and, 2) instead of sutures, the arch was attached to the ventricle with a row of steel pins in each foot. Length-tension curves were developed by increasing the muscle segment length and recording the induced changes in developed tension or contractile force (CF). Contractile force recorded in grams obtained at any length was normalized for the increased wall thickness accompanying hypertrophy by dividing recorded CF by the product of the distance across the row of steel pins and the wall thickness of the ventricle measured along the pin tracks, thus expressing the data in grams of CF per square centimeter of muscle. A beginning point on the length-CF curve was established in each dog as follows. Prior to attachment and with no loading forces on the arch, a zero force base line was established on the recorder. The two rows of pins were then adjusted 13 mm apart and the arch was attached to the ventricle. The diastolic portion of the force tracing was usually offset from the zero force base line. The diastolic portion of the CF trace was then adjusted to the zero force base line by length adjustments to the muscle segment. By this maneuver, the vector sum (resultant) of forces acting on the arch during diastole was made equal to zero, indicating that at this point the arch imposed no additional preload on the ventricle. It was assumed that by these adjustments a starting point on the length-CF curve was defined that was common to all dogs and was equivalent to the intrinsic preload operating on the ventricle. Details of recording the length-CF curve have been previously reported (16). To test the assumption that the length adjustments described above resulted in a starting point on the length-CF curve equivalent to that operating in the ventricle, in four dogs the heart was arrested in diastole with methacholine chloride, 50-100 pg/kg, injected rapidly through the venous cathe ter. The arch was attached to the arrested heart and a length -CF curve was developed. In this case, as opposed to when the arch was attached to the beating heart, the diastolic portion of the CF trace was not offset from the zero force base line, and no length adjustmen ts were m ade. After the length-CF cu.rv.e wa s recorded, the arch was removed and 1 h later was reattached in the same dog in the usual manner. After length was adjusted as described above, the length- ,CF curve was again re-

AND

GLUCAGON

H691

corded. These experiments allowed us to attach the arch consistently during diastole and compare the recorded length-CF curve to a similar curve obtained in the same dog when the arch was attached to the beating heart. Dose-response curves. To evaluate the ability of the ventricle in heart failure to respond to positive inotropic stimuli, dose-response curves for norepinephrine, isoproterenol, calcium, and glucagon were determined. Induced changes in CF are reported as the maximum percent change from control (%ACF), with the muscle length fixed at 100% Las. Norepinephrine and isoproterenol were given in doses of the base: 0.0125, 0.025, 0.05, 0.10, 0.20, 0.40, 0.80, 1.60, and 3.20 pg/kg. Calcium was administered in the form of CaCl, in doses of calcium of 1.O, 2.0, and 4.0 mg/kg. Glucagon was administered by bolus injection in doses of 10, 20, and 40 pg/kg. All injections were made through the Swan-Ganz catheter. Following the administration of each dose all recorded variables were allowed to return to control values. One hour was allowed to elapse before the next drug was given, with drugs being given in all permutations of order. During this l-h period, blood pH was monitored and adjusted to the stated range. Acute elevation of left ventricle diastolic pressure. In these experiments the influence of acutely elevated left ventricular diastolic pressure (LVDP) on the length-CF curve and the contractile response to norepinephrine and isoproterenol were determined. In seven normal dogs a length-CF curve and the CF response to norepinephrine and isoproterenol at doses of 0.05, 0.2, and 0.8 ,ug/kg were first determined at intrinsic LVDP measured with a Millar Mikrotip PC-350A pressure catheter inserted into the left ventricle through the right carotid artery. After these determinations the arch was removed from the ventricle and a l-h stabilization period was allowed. Following this period, a 6% dextran in saline solution was administered intravenously by rapid drip through the femoral vein until a LVDP of 25 mmHg was obtained. The dip was adjusted to maintain LVDP at this level. The arch was then reattached to the ventricle and a second length-CF curve and set of dose-response curves were recorded. To control for the effect of the time elapsed between the two sets of measurements and for the variability produced by removing and reattaching the arch, a similar group of experiments was conducted in seven additional dogs in which the arch was removed and replaced after a l-h period. In this group of dogs no dextran was given and LVDP remained constant. Measurement of the ventricles. At the completion of the experiment the heart was arrested in diastole with pentobarbital injected directly into the LV and removed from the chest. The atria and free wall of the right ventricle were trimmed away, leaving the LV and septum intact. The LV was weighed and then sliced through in a plane perpendicular to the long axis and passing through both sets of holes produced by the coupling pins. Left ventricular wall thickness (LVh) was measured at both sites of pin penetration, and left ventricular inside diameter (LW was measured across

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H692

W.

the chamber at midpoint in the plane of the short axis. The right ventricle was weighed and then sliced through midway along the long axis, and wall thickness (RVh) was measured. Analysis of data. Data were analyzed using Student’s unpaired t test and linear regression analysis according to Snedecor and Cochran (19). RESULTS

Table 1 summarizes the changes in ventricular geometry associated with this model of heart failure. Left and right ventricular hypertrophy is evident by the significant increases in the ratio of left and right ventricular weight to body weight. Additionally, left ventricular wall thickness was significantly increased. Heart rate, measured with the dog under pentobarbital anesthesia, was not significantly different from normal in the animals with congestive heart failure (CHF) (Table 1), nor in the seven dogs with acutely created arteriovenous shunt (mean, 173.7 t 11.5 beats/min). This lack of difference in heart rate among the three groups under the conditions of the experiment would seem to preclude the necessity of cardiac pacing in order to obtain comparable heart rates among the three groups. The animals with CHF had a significantly lower diastoli .c arterial pressure than normal (Ta .ble 1). This was also true for the animals with the acute shunt (AS) (mean 55.8 t 3.5 mmHg). Systolic arterial pressure was not different am .ong the three groups. Pulmonary wedge pressure was significantly elevated in the animals with CHF with a mean value of 16.7 t 1.4 mmHg. In these dogs PWP ranged from 8 to 25 mmHg (normal range 3.5-6 mmHg); use of this measurement as an index of the severity of CHF would suggest that the CHF group was nonhomogenous with respect to the degree of failure. Pulmonary wedge pressure in the dogs with the AS averaged 4.5 t 0.7 mmHg (range 2.06.3 mmHg), a value not significantly different from normal. Length- tension relationsh .ips. F ‘igure 1 shows mean length-CF curves obtained from the three groups of dogs in a manner described previously in detail (16). Briefly, the curve for each dog was plotted with the maximum recorded length-dependent CF set to 100% Lax. The mean curve was constructed by raising a line vertically to the abscissa at each 5% increment of Lax and measuring CF from each individual length-CF TABLE

1. Measurements

Normal

(n = 17) CHF

(n = 14) P Values thickness; anesthesia;

of left and right ventricle,

H.

NEWMAN

curve at its intersection with this vertical line. The top panel of Fig. 1 shows CF plotted as grams of CF and is used as an index of total ventricular force-generating capacity. There were no significant differences between the curves obtained from the normal group and those obtained from the acutely shunted dogs. Comparison of the dogs with CHF to the normal group showed that CHF was associated with a significant shift up the CFlength curve. In the normal group, the initial point on the length-CF curve averaged 62.4 t 1.0% Lax whereas in CHF the initial point was 83.4 t 2.7% Lax (P < 0.001). Included in this mean value are four dogs at 90% LaX or greater. In one of these four animals with the highest PWP, 25 mmHg, and 5 liters of ascitic fluid, only a descending limb of the length-CF curve was obtained. This animal was assumed to be functioning at 100% Lax and the individual curve was plotted accordingly. The normal and CHF groups were also significantly different in the amount of CF measured at the initial point of the length-CF curve (56.8 t 4.5 g in the normal group vs. 80.2 t 9.4 gin CHF, P < 0.05). The length-CF relation for grams of CF was below the normal in CHF. Values of CF at corresponding %L,, were significantly different between the two groups (P c 0.05). The mean length-CF curve obtained from the dogs with the acute shunt was not significantly different from that obtained from the normal group. The bottom panel of Fig. 1 shows the mean lengthCF curves obtained from the three groups of dogs with CF normalized per unit of muscle acting on the strain gauge arch. There was no significant difference between the normal and AS group. However, at any %L,,, CF in g/cm* was significantly less (P < 0.05) in the CHF group than in the normal group. Figure 2 shows the results of linear regression analysis of the initial point on the length-CF curve expressed as %L,, versus two different indices of preload obtained from the 13 animals with CHF in which PWP was recorded. Figure 2A shows the relationship between initial %L,, and PWP. A significant direct linear correlation was found between these two variables (r = 0.669, P < 0.01). In Fig. 2E3the initial %L,, is plotted against an index of left ventricular loading force determined by the product of the pressure and the square of the internal chamber radius (11, 17, 29). In this case it was assumed that PWP reflects LVDP, and this value was multiplied by the square of one-half the inside ventricular diameter (LVd) obtained from mea-

heart rate, and blood pressures

23.8 to.86

113.1 54.6

4.76 kO.06

3.22 kO.13

1.35 20.05

38.5 rd.7

1.61 kO.05

0.75 20.01

125.0/96.8 24.815.1

162.1 k5.7

5.1 kO.5

25.3 20.79

133.1 t3.3

5.38 20.16

4.43 kO.14

1.55 kO.02

45.5 t1.8

1.83 kO.07

0.77 kO.02

117.6/60.7 k5.715.13

159.7 t9.5

16.7 k1.4

co.01

co.01

co.01

co.01

NS

co.01

are means t SE. BW, body weight; LVW, left ventricular RVW, right ventricular weight; RVh, right ventricular PWP, pulmonary wedge pressure; CHF, congestive heart

co.01 weight; LVd, wall thickness; failure.

NS

NWO.01

left ventricular ABP, arterial

NS

~0.001

diameter; LVh, left ventricular blood pressure; HR, heart rate

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wall under

HEART

FAILURE:

LENGTH-TENSION,

WORMe-0

17

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AND AGONISTS,

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CA2+,

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90

100

1

FIG. 1. Mean length-CF curves obtained from normal (Norm) dogs, from dogs with acute aortocaval shunts (AS), and from dogs with congestive heart failure (CHF). Values + SE and stars indicate significant differences.

110

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100

90

80

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r = 0.837

p < 0.01

P< 0.001

0

10

14

18

PWP (mm ag)

22

26

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100 PWP r(LVd/2)2

150

FIG. 2. A.- relationship between initial %Lax on individual length-CF curves obtained from dogs with CHF and pulmonary wedge pressure (PWP). B: relationship between initial %L,, and

an index of loading force (see text). Line is line of best fit calculated by linear regression analysis; r, correlation coefficient.

surement of the LV at autopsy. Including a radius term in the preload index significantly improved the correlation coefficient (r = 0.837 vs. r = 0.669 (P c 0.001)

when PWP alone is used as an index of preload), indicating a greater inclusion of variance in the equation, i.e., 45%(0.669)* vs. 70%(0.837)*.

Downloaded from www.physiology.org/journal/ajpheart at Macquarie Univ (137.111.162.020) on February 14, 2019.

H694

W.

Dose-response relationships. Figure 3 shows mean dose-response curves of arterial diastolic blood pressure (ADBP), heart rate, and %ACF for norepinephrine administration obtained from the three groups of dogs. At all dose levels of norepinephrine, ADBP was significantly less (P < 0.05) than the normal group in both the CHF and AS groups. However, the increment in ADBP associated with each dose was not significantly different among the three groups. Similarly there was no significant difference among the three groups in the response of heart rate to drug administration. On the other hand, %ACF was significantly less (P c 0.05) in the CHF group than in either the normal or AS group at all dose levels of norepinephrine. The same pattern of response was seen in the isoproterenol dose-response curves, i.e., no difference in the response of heart rate and ADBP among the three groups and a significantly depressed response of CF in the CHF group. This response is seen in Fig. 4. Figure 5 shows mean doseresponse curves for calcium (left) and glucagon (right). With either agent, no significant difference was observed among the three groups in the response of heart rate or ADBP; however, the response of CF was significantly depressed (P < 0.05) in the CHF group at all dose levels of either agent. Acute elevation of left ventricular diastolic pressure. Figure 6 shows the influence of acutely elevated LVDP on the length-CF relationship and the response of CF to three doses of norepinephrine and isoproterenol. Figure 6A shows the mean length-CF curve from seven *coA? l

NORM O-0 AS 0 -0 CNF A-A

I t

FIG.

breviations

N@RM 0-0 AS 0 -0 A-A

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6 11

4. Mean dose-response are as in Fig. 3.

NORM. -0 AS o-o CNF A-A

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curves

for

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(Isup).

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(left)

and

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200-

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3. Mean dose-response curves of aortic sure, heart rate, and contractile force (%ACF) Abbreviations and symbols are as in Fig. 1. FIG.

diastolic blood presfor norepinephrine.

I

1

10

2.0

I

ca++ MVh8

FIG.

glucagon

5. Mean

(right).

dose-response Abbreviations

20 CLUCACON

I 40 uvCg

curves for calcium are as in Fig. 3.

Downloaded from www.physiology.org/journal/ajpheart at Macquarie Univ (137.111.162.020) on February 14, 2019.

(Ca2+)

HEART

FAILURE:

LENGTH-TENSION,

AND

AGONISTS,

CA'+,

n

CONTROL,

-P

DEXTRAN , LVDP = 25 IIMIN,

AND

H695

GLUCAGON

LVDP = 3.2 2 1.0 ratNg

FIG. 6. Mean length-CF curves (A) and dose-response curves (B) showing response of CF to norepinephrine (NE) and isoproterenol (Isup), obtained from 7 normal dogs before and after left ventricular diastolic pressure (LVDP) was raised to 25 mmHg by dextran infusions. Mean initial %L,, was 62.3 + 4.2% at intrinsic LVDP and significantly increased to 74.2 + 5.2% at an LVDP of 25 mmHg.

0:os

012 DOSE (us 1 b)

018

dogs obtained at the intrinsic LVDP (mean 3.2 t 1.0 mmHg) and the mean length-CF curve obtained in the same animals after LVDP was increased to 25 mmHg by an infusion of an average of 1.7 liters of 6% dextran. Increasing LVDP produced a significant shift up the length-CF curve from a mean initial point of 62.3 t 4.27% Lax in the control state to 74.2 t 5.2% Lax when LVDP was 25 mmHg (P < 0.05). There was no difference in CF developed at any given %L,, between the control and elevated LVDP state. Similarly, acute elevation of LVDP was not associated with a significant change in the response of CF to norepinephrine or isoproterenol (Fig. 6B). Only one point, isoproterenol 0.05 pg/kg, on either dose-response curve was significantly influenced (P < 0.05) by acutely elevated LVDP. Figure 7 shotis the reproducibility of length-CF and dose-response curves recorded from the same animals. The two sets of length-CF and dose-response curves were recorded 1 h apart. Left ventricular diastolic pressure did not change in these experiments, averaging 3.5 t 1.0 mmHg control and 3.5 t 1.0 mmHg after an additional l-h interval in these seven dogs. The mean initial points on the length-CF curve were 67.3 t 2.9% Lax and 68.3 t 3.25% Lax for the control and plus-l-h measurements, respectively. These values were not significantly different. Similarly, no signifi-

cant change was observed in the amount of CF recorded at any given %L,, between the two sets of curves. Figure 7B shows the two sets of dose-response curves of CF in response to norepinephrine and to isoproterenol recorded in the same animals at a l-h interval. The only point significantly different from control was at a norepinephrine dose level of 0.5 pg/kg (P < 0.05). Cardiac arrest with methacholine. Figure 8 shows the mean length-CF curves obtained from four normal dogs with and without cardiac arrest induced by methacholine. There was no significant difference in CF developed at any corresponding %L,, or in the initial %L,, recorded when the arch was attached during diastolic arrest, 66.5 t 6.2% Lax, and that recorded when the arch was attached to the beating heart, 68.5 t 3.2% Lax. DISCUSSION

When chronic pressure or volume overloading is imposed on the heart, there are three principal compensatory mechanisms intrinsic to the ventricle which are all capable of increasing the force of ventricular contraction collectively or independently and which provide a limited reserve for the maintenance of cardiac output: 1) length-tension, 2) ventricular hypertrophy,

Downloaded from www.physiology.org/journal/ajpheart at Macquarie Univ (137.111.162.020) on February 14, 2019.

H696

W.

H.

NEWMAN

200

/V’

I

-*

CONTROL, LVDP= 3.5 f 1.0 mnlig

0-a

+ 1 hr.,

LVDP = 3.5 t

LO mmflg

obFIG. 7. Mean length-CF and dose-response curves tained from 7 normal dogs at intrinsic LVDP at a l-h was 67.3 + 2.9% for control and interval. Initial %Lnax 68.3 + 3.25% after 1 h.

0.2

0*05

0:s

DOSE (“g/kg)

zoo-

O-0

CONTROL

l -0

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150cf\rrD ‘f loo50 1 L 0

I 60

1 70

I 80

1 90

I

r-

100

110

%Lx 8. Mean length-CF curves obtained from 4 normal dogs and without (control) cardiac arrest induced by methacholine. breviations are as in Fig. 1. FIG.

with Ab-

and 3) increased contractility or positive inotropism. The present experiments were designed to directly evaluate the interrelations of these three mechanisms

in the force-generating capacity of the left ventricle in a dog model of chronic volume overload that produces the signs of ventricular hypertrophy and heart failure. Left ventricular hypertrophy was indicated by a statistically significant increase in LV mass, wall thickness, and LV mass-to-body weight ratio in dogs with chronic a-v fistulas. Signs of heart failure in these dogs incIuded a significantly elevated PWP along with ascites, pleural effusions, and limb edema. The force-generating capacity of these hypertrophied ventricles was examined in the basal state, i.e., during pentobarbital anesthesia but before drug injections, in terms of the length-tension relationship. The ability to increase CF in response to inotropic stimuli was also determined. The results indicate that chronic volume overload is associated with a shift up the length-CF curve in a manner directly related to the increased preload on the LV. This conclusion is supported by the finding that the mean initial point on the length-CF curve in normal dogs was 62.4 t 0.1% Lax and that following chronic volume overload, this mean point had shifted to 83.4 t 2.7% Lax. The initial point on the length-CF

Downloaded from www.physiology.org/journal/ajpheart at Macquarie Univ (137.111.162.020) on February 14, 2019.

HEART

FAILURE:

LENGTH-TENSION,

AND

AGONISTS,

CA2+,

curve in each individual dog with chronic volume overload was significantly correlated with the corresponding PWP, an index of left ventricular preload pressure, and this correlation was significantly improved when preload pressure was converted to an index of preload force by including a term for LV radius. We view the two sets of length-CF curves obtained from each experimental group (Fig. 1) in the following manner. When CF in grams is plotted against %LaX, the resulting curve is considered to be an index of the force-generating capacity of the entire LV at any %La, because the CF recorded reflects the force generated by the total area of muscle bounded by the steel pins on the strain gauge arch. When CF in grams is normalized for LV wall thickness by dividing CF by the product of LVh and the distance across the coupling pins (g/cm2) and plotted against %LaX, the resulting curve is considered to represent an index of forcegenerating capacity of each unit of muscle (cm2> in the LV wall. This length-CF curve, corrected for muscle area, is considered to reflect the inotropic state of the cardiac muscle. When CF was normalized for LV wall thickness, all points on the length-CF curve obtained from dogs with chronic volume overload were significantly less than corresponding points on the length-CF curve obtained from the normal group. Similarly, total CF in grams at any point along the mean length-CF curve obtained from dogs with chronic volume overload was significantly less than corresponding values obtained from the normal group. Taken together these two findings suggest that each unit of muscle in the hypertrophied failed ventricle has less force-generating potential than normal and that the increased number of these weaker units associated with hypertrophy was not sufficient to return the length-CF of the entire LV to the normal range of force-generating potential. These findings are compatible with the view that, in these experiments, chronic volume overload producing the signs of heart failure is associated with a depression of the ventricular contractile state, i.e., muscle failure. These findings support those of Zucker et al. (30), who found depression of LV dP/& normalized for LVDP in this same model of chronic volume overload. Taylor et al. (25), on the other hand, found no evidence of LV muscle depression in this model as judged by tensionvelocity relationships. The difference between the findings of Zucker et al. (30) and ourselves and the finding of Taylor et al. (25) may relate to the duration of volume overload. In our experiments the mean duration of overload was 105 days and in those of Zucker et al. (30) it was 58 days, both longer than the mean duration of 40 days reported by Taylor et al. (25). The suggestion that the duration of overload may play a significant role in chronic volume overload models is supported by the findings of Taylor et al. (26), which were obtained from dogs with chronic aortic regurgitation. In their experiments, dogs with aortic regurgitation for 100 days showed no depression of V,,, or max LV dPldt; however, when aortic regurgitation was present for an average of 329 days, V,,, and max LV dPldt were depressed. It is interesting to compare these results with those we have previously reported, which were obtained from

AND

GLUCAGON

H697

a dog model of stable volume overload hypertrophy without signs of heart failure (16). In our previous study, volume overload was induced by chronic heart block and resulted in changes in LV weight, wall thickness, and diameter that were similar to those in the present studies; however, the dogs with heart block showed no signs of heart failure. Length-CF curves from the dogs with heart block and stable hypertrophy were normal when expressed as CF in g/cm2 and shifted upward compared to normal when plotted as total CF in grams. These findings are shown in Fig. 9. We recognize that the two models are not strictly comparable in that the heart block model is primarily a low cardiac output state and the aortocaval fistula model is a high output state. However, both models involve a volume determinant as the principal cause of overload and both models result in eccentric hypertrophy of the LV. Additionally, these results are in agreement with results reported from papillary muscles obtained from models of volume overload-induced hypertrophy and hypertrophy with failure. Cooper et al. (5) found normal tension developed (g/mm2) at any %Lax in papillary muscles obtained from cats with volume overload hypertrophy induced by atria1 septal defects. Papillary muscles obtained from animals with pressure overload hypertrophy alone or hypertrophy and heart failure show depressed length-tension curves (10, 20, 21, 23,

24) The above findings along with those previously reported support the view that in heart failure the basal contractile state of the ventricle is depressed. However, since the third intrinsic mechanism acting to maintain cardiac output involves the ability of the ventricular muscle to increase its force of contraction in response to positive inotropic stimulation, we determined dose-response curves for various positive inotropic agents. These experiments are of particular importance in regard to the P-sympathetic agonists, norepinephrine and isoproterenol, inasmuch as increased activity of the sympathetic nervous system is thought to contribute to the maintenance of cardiac output during heart failure (13). Our data indicate that the positive inotropic response of the left ventricle (i.e., increase in CF) in response to exogenous administration of these two P-agonists was depressed in heart failure, whereas the responses of heart rate and blood pressure were not altered by heart failure. These findings are in agreement with our preliminary report in a smaller group of animals (l5), and the depressed inotropic response has been confirmed by another group of investigators using a different index of inotropism, i.e., dP/& measurements, in the same model of heart failure (31). In the present investigation, dose-response curves for two other positive inotropic agents, calcium and glucagon, which do not act by P-receptor stimulation, were also determined. A similar pattern was seen in response to these two agents, i.e., a depressed response of CF in heart failure while the blood pressure and heart rate responses were not significantly different from those obtained in the normal group. It seems unlikely that the depressed response of CF in the dogs with heart failure could be due to altered hemodynamics associated with the model because the responses of heart rate

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H698

W.

FIG. 9. Length-CF relationships mal dogs and dogs with stable congestive heart failure (CHF) overload.

1

I 70

I

I 80

I

I 90

I

I 100

I

H.

NEWMAN

derived from norhypertrophy (SH) or from chronic volume

A

%l W1X

and blood pressure were not different from normal and because the dose-response curves were not altered in the dogs shunted acutely. Further, infusion of an average of 1.7 liters of fluid in a group of dogs in order to acutely elevate LVDP to 25 mmHg did not alter the dose-response curves for norepinephrine and isoproterenol. Although these experiments cannot rule out a specific change in P-receptor number or affinity in heart failure, taken collectively, the response to these four agents suggests that an intrinsic defect in the excitation-contraction coupling mechanism is associated with heart failure in this model. The defect does not seem to be specific for the P-recept0.r adenylate cyclase axis because the response to glucagon, which does not stimulate the P-receptor but activates adenylate cyclase (12)) was also depressed and, further, the response to calcium, which does not act’through the P-receptor or, to our knowledge, activate adenylate cyclase, was depressed in heart failure. The data suggest that the cause of the depressed response of CF in heart failure lies at some common site along the excitation-contraction coupling pathway, such as the activity of myosin ATPase, or calcium binding and release by the sarcoplasmic reticulum. In this regard, it has been shown that heart failure is associated with a depressed myosin ATPase activity (1, 2) and alterations in calcium binding by the sarcoplasmic reticulum (10, 14).

Previous reports dealing with aspects of sympathetic function in heart failure have indicated that this disorder is associated with high circulating levels of norepinephrine (4, 28) while myocardial norepinephrine content is depleted (3, 22). Studi .es of cardioa ccelerator nerve stimulation in dogs with heart failure indicated a depressed response of CF t3 nerve stimulation but normal response to a single dose of exogenous norepinephrine (8). In papillary muscle preparation from failure models, force development in response to norepinephrine was found to be normal (9) or greater than normal (21). The ability of glucagon to augment the force of contraction in papillary muscle from failed cat hearts has been shown to be depressed (9), whereas in the in vivo failing cat ventricle the response was normal (18). Our present experiments cannot resolve these conflicts and in fact may be unrelated, because the previous findings were obtained in models of pressure overload heart failure, while whereas the present report deals with volume overload failure. Nonetheless, the previous reports of reduced myocardial norepinephrine content and contractile response to sympathetic nerve stimulation, along with the reduced response of CF to exogenous norepinephrine and isoproterenol reported here, suggest that the inotropic response to sympathetic stimulation is reduced in heart failure. We recognize the complexity of recording the force of muscle contraction with a strain gauge arch from the

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HEART

FAILURE:

LENGTH-TENSION,

AND

AGONISTS,

CA’+,

in situ left ventricle (16, 17). To preclude the possibility that altered hemodynamics associated with the aortocaval fistula may have influenced the strain gauge recordings, all experiments were repeated in a group of animals in which the fistula was created on the day of the experiment. In this group, neither the length-CF curves nor the dose-response curves for the four positive inotropic agents were significantly different from those obtained in the normal group of dogs. Further, the influence of elevated LVDP was evaluated by acutely raising the LVDP to 25 mmHg, a value corresponding to the highest PWP obtained in the heart failure group. Dose-response curves of CF for norepinephrine and isoproterenol were not significantly influenced by the acute elevation of LVDP. Similarly, CF recorded at any %LaX following acute elevation of LVDP was not significantly different from that recorded at the corresponding %L,, at intrinsic LVDP. Additionally, removal and replacement of the strain gauge arch after a l-h time interval did not alter the dose-response or length-CF relationships. Moreover, the initial point on the length-CF curves recorded with dogs with heart failure was significantly correlated with indices of preload. Finally, cardiac arrest with methacholine, which permitted consistent attachment of the arch during diastole, did not influence the length-CF curve. These results tend to support the adequacy of the strain gauge methodology for the purposes of this study. In summary, the results of-this study indicate that chronic volume overload of sufficient duration is asso-

AND

H699

GLUCAGON

ciated with depression of the contractile state of each unit of myocardium and that the increased number of these weakened units associated with hypertrophy does not summate to return the total force of ventricular contraction to normal. Compensation for the imposed increase in ventricular load is brought about primarily by a shift up the length-CF curve. Further, dose-response curves of CF for a variety of positive inotropic agents are depressed, suggesting a generalized depression of the failed myocardium to respond to inotropic stimulation. The depressed CF-response to P-agonist while the responses of heart rate and blood pressure were unaltered in this model is particularly significant. Such findings suggest that high sympathetic tone accompanying heart failure may lead to increased peripheral resistance in the normal manner as well as a normal increase in heart rate. These two actions would act co11.ectively to load and increase the oxygen consumption of the failing ventricle, which does not respond to this high sympathetic tone with the normal increase in the inotropic state. Therefore the role of the sympathetic nervous system in heart failure would seem open to question. The author acknowledges the excellent technical assistance of George 0. Washington and Ms. Sandra Erskine and the excelsecretarial service of Ms. Marie Truesdell. This work was supported by Public Health Service Grant HL14545 and by grants from the South Carolina Heart Association.

Mr. lent

Received

13 February

1978; accepted

in final

form

20 July

1978.

REFERENCES 1. ALPERT, N. R., AND M. S. GORDON. Myofibrillar adenosine triphosphatase activity in congestive heart failure. Am. J. Physiol. 202: 940-946, 1962. 2. CHANDLER, B. M., E. H. SONNENBLICK, J. F. SPANN, AND P. E. POOL. Association of depressed myofibrillar adenosine triphosphatase and reduced contractility in experimental heart failure. CircuZation Res. 21: 717-725, 1967. 3. CHIDSEY, C. A., E. BRAUNWALD, A. G. MORROW, AND D. T. MASON. Myocardial norepinephrine concentrations in man: Effects of reserpine and congestive heart failure. New Engl. J. Med. 269: 653-658, 1963. 4. CHIDSEY, C. A., D. C. HARRISON, AND E. BRAUNWALD. Augmentation of the plasma norepinephrine response to exercise in patients with congestive heart failure. New Engl. J. Med. 267: 650-654, 1962. 5. COOPER, G., IV, F. J. PUGA, K. J. ZUJKO, C. E. HARRISON, AND H. N. COLEMAN III. Normal myocardial function and energetics in volume-overload hypertrophy in the cat. CircuZation Res. 32: 140-148, 1978. 6. COOPER, G., IV, R. M. SATAVA, C. E. HARRISON, AND H. N. COLEMAN III. Mechanism for the abnormal energetics of pressure-induced hypertrophy of cat myocardium. Circulation Res. 33: 213-223, 1973. 7. COOPER, G., IV, R. M. SATAVA, C. E. HARRISON, AND H. N. COLEMAN III. Normal myocardial function and energetics after reversing pressure-overload hypertrophy. Am. J. Physiol. 226: 1158-1165, 1974. 8. COVELL, J. W., C. A. CHIDSEY, AND E. BRAUNWALD. Reduction of the cardiac response to postganglionic sympathetic nerve stimulation in experimental heart failure. CircuZation Res. 19: 5L 56, 1966. 9. GOLD, H. K., K. H. PRINDE, G. S. LEVEY, AND S. E. EPSTEIN. Effects of experimental heart failure on the capacity of glucagon to augment myocardial contractility and activate adenyl cyclase. J. CZin. Invest. 49: 999-1006, 1970.

10. HARIGAYA, S., AND A. SCHWARTZ. Rate of calcium binding and uptake in normal animal and failing cardiac muscle. CircuZation Res. 25: 781-794, 1969. 11. HEFNER, L. L., L. T. SHEFFIELD, G. C. COBBS, AND W. KLIP. Relationship between mural force and pressure in the left ventricle of the dog. CircuZation Res. 11: 654-663, 1962. 12. LEVEY, G. S., AND S. E. EPSTEIN. Activation of adenyl cyclase by glucagon in Ca+ and human heart. Circulation Res. 24: 151-156, 1969. 13. MASON, D. T. Regulation of cardiac performance in clinical heart disease. Am. J. CardioZ. 32: 437-448, 1973. 14. MCCOLLUM, W. B., C. CROW, S. HARIGAYA, AND A. SCHWARTZ. Calcium binding by cardiac relaxing system isolated from myopathic Syrian hamsters. J. MOL. CeZZuZar CardioZ. 1: 445-457, 1970. 15. NEWMAN, W. H. A depressed response of left ventricular contractile force to isoproterenol and norepinephrine in dogs with congestive heart failure. Am. Heart J. 93: 216-221, 1977. 16. NEWMAN, W. H. Contractile state of hypertrophied left ventricle in long-standing volume overload. Am. J. PhysioZ. 234: H88H93, 1978 or Am. J. Physiol.: Heart Circ. PhysioZ. 3: H88-H93, 1978. 17. NEWMAN, W. H., AND R. P. WALTON. Strain gauge arch recordings from an acutely ischemic area of the left ventricle. J. AppZ. Physiol. 23: 398-400, 1967. 18. NOBEL-ALLEN, N., M. KIRSCH, AND B. R. LUCCHESI. Glucagon: Its enhancement of cardiac performance in the cat with chronic heart failure. J. PharmacoZ. Exptl. Therap. 187: 475-481, 1973. 19. SNEDECOR, G. W., AND W. G. COCHRAN. StatisticaL Methods. Ames, Iowa: Iowa State Univ. Press, 1967. 20. SPANN, J. F. Heart failure and ventricular hypertrophy altered cardiac contractility and compensatory mechanisms. Am. J. CardioZ. 23: 504-510, 1969. 21. SPANN, J. F., R. A. BUCCINO, E. H. SONNENBLICK, AND E. BRAUNWALD. Contractile state of cardiac muscle obtained from

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W. H. NEWMAN

H700 cats with experimentally produced ventricular hypertrophy and heart failure. CircuZution Res. 21: 341-354, 1967. 22. SPANN, J. F., C. A. CHIDSEY, AND E.‘BRAUNWALD. Reduction of cardiac stores of norepinephrine in experimental heart failure. Science 145: 1439-1441,1964. 23. SPANN, J. F., J. W. COVELL, D. L. ECKBERG, E. H. SONNENBLICK, J. Ross, JR., AND E. BRAUNWALD. Contractile performance of the hypertrophied and chronically failing cat ventricle. Am. J. Physiol. 24. SPANN,

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R. R., AND B. E. HO-INS.

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J. F., D. T. MACON, AND R. F. ZELIS. The altered performance of the hypertrophied and failing heart. Am. J. Med. Sci. 258: 291-303, 1969. 25. TAYLOR, R. R., J. W. COVELL, AND J. Ross, JR. Left ventricular function in experimental aorto-caval fistula with circulatory congestion and fluid retention. J. Clin. Invest. 47: 1333-1342, 1968. 26. TAYLOR,

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experimentally induced chronic aortic regurgitation. Cardiouascular Res. 6: 404-414, 1972. TURINA, M., W. D. BUSSMANN, AND H. P. KRAYENBUHL. Contractility of the hypertrophied canine heart in chronic volume overload. Cardiovascular Res. 3: 486-495, 1969. VOGEL, J. H. K., AND C. A. CHIDSEY. Cardiac adrenergic activity in experimental heart failure assessed with beta receptor blockade. Am. J. Cardiol. 24: 198-208, 1969. WEBER, K. T., J. S. JANICKI, R. C. REEVES, AND L. L. HEFNER. Factors influencing left ventricular shortening in the isolated canine heart. Am. J. Physiol. 230: 419-426, 1976. ZUCKER, I. H., A. M. EARLE, AND J. P. GILMORE. The mechanism of adaptation of left atria1 stretch receptors in dogs with chronic congestive heart failure. J. CZin. Invest. 60: 323-331, 1977. ZUCKER, I. H., AND J. P. GILMORE. Depressed cardiac response to catecholamines in dogs with chronic volume overload (Abstract). CircuZation 55-56, Suppl3: 54, 1977.

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Volume overload heart failure: length-tension curves, and response to beta-agonists, Ca2+, and glucagon.

Volume overload heart failure: length-tension curves, and response to P-agonists, Ca2+, and glucagon WALTER H. NEWMAN Department of Pharmacology, Medi...
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