Volume

123

Number

1

Pimobendan in CHF

canine ventricular muscle. J Pharmacol Exp Ther 1982;221: 71583. 25. Endoh M, Yanagisawa T, Taira N, Blinks JR. Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle. Circulation 1986;73 (suppl 111):111117-31.

Metabolic and cardiovascular from ,&adrenergic blockade congestive heart failure

26. Scholz H, Meyer N. Phosphodiesterase-inhibiting properties of newer inotropic agents. Circulation 1986;73(suppl III):I1199-111106. 27. Weber KT, Kinasewitz GT, Janicki JS, Fishman AP. Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation 1982;65:1213-23.

benefits deriving in chronic

Ten patients with congestive heart failure were given metoprolol (50 mg/day) or placebo during double-blind, crossover, randomized study. After a run-in period of 4 weeks, metoprolol and placebo were administered over a period of 3 months, which was separated by a washout period of 4 weeks. At the end of the run-in, metoprolol, and placebo periods, all patients underwent metabolic (oral glucose tolerance and hyperinsulinemic glucose clamp tests) and noninvasive cardiologic (New York Heart Association classification, bimodal echocardiographic left ventricular end-diastolic determination, maximal oxygen consumption, left ventricular radionuclide ejection fraction) tests. Our results show that ,8-adrenergic blockade significantly enhances insulin-mediated suppression of hepatic glucose output (p < 0.005) and increase in glucose uptake (p < 0.01) with a concurrent improvement in New York Heart Association functional class (p < 0.05) and the multistage exercise treadmill test score (p < 0.05). After administration of metoprolol all changes in glucose turnover parameters were found to correlate with the decrease in basal plasma free fatty acid levels. In conclusion, our findings conflrm the beneficial cardiologic effects of @adrenergic blockade in congestive heart failure and demonstrate that metoprolol is also useful for reverslng the metabolic damage caused by exaggerated plasma norepinephrine levels. (AM HEART J 1992;123:103.)

a

Giuseppe Paolisso, Antonio Gambardella, Giuseppe Marrazzo, Mario Verza, Paola Teasuro, Michele Varricchio, and Felice D’Onofrio. Naples, Italy

Numerous studies have demonstrated a significant increase in plasma catecholamine concentrations in patients with heart failure.lT6 It has also been shown that plasma norepinephrine levels may be used as a guide for determining the prognosis in these patients3 and that there is an inverse relationship

From the Institute di Gerontologia e G&atria, wale, Terapia Medica e Malattie de1 Metabolismo, Radioisotopica, First Medical School, University Received

for publication

Reprint requests: tria, 1st Medical 411133646

March

Dr. Giuseppe School, Piazza

Istituto di Medicina GenCattedra di Diagnostica of Naples.

20, 1991;

accepted

Paolisso, Miraglia

Istituto di Gerontologia 2, I-80138 Napoli, Italy.

July

22, 1991. e Geria-

between plasma norepinephrine levels and P-receptor density. It8 Among the guidelines for therapy of heart failure, ,B-adrenergic-blocking agents have been shown to be useful inasmuch as they allow hemodynamic and clinical improvement, probably because of an upregulation of myocardial /3 receptors.6-8 More recently, ,8-adrenergic blockade has been shown to reduce plasma free fatty acid (FFA) levels, thus improving glucose transport in skeletal muscle of diabetic rats.s Previous studies have also demonstrated chronic congestive heart failure to be an insulin-resistant state, mainly because of an increase in plasma FFA levels after plasma norepinephrine levels have become exaggerated.iO*il In light of such

103

104

Paolisso et al.

Table

1. Clinical

Patients 1 2 3 4 5 6 7 8 9 10

American

characteristics Age fyr)

58 62 47 61 67 49 51 55 52 56 55.8 + 2.0

Sex OfIF) M M F M F F M M F M

of the subjects BMI (kg/m? 22 24 22 22 25 22 21 26 22 23 22.9 f 0.5

NYHA class II-III III III II-III II-III II-III II-III III II-III III

January 1992 Heart Journal

studied Digitalis (mdday)

Furosemide fmglday)

0.125 0.250 0.250 0.125 0.125 0.125 0.125 0.250 0.125 0.250 0.175 f 0.020

50 50 50 25 25 25 25 50 25 50 37.5 -+ 4.17

Fasting plasma norepinephrine (pmollL) 5.44 6.06 5.65 5.01 5.18 4.47 4.69 5.98 5.51 5.79 5.38 + 0.16

Cause

of heart

failure

Dilative cardiomyopathy Dilative cardiomyopathy Dilative cardiomyopathy Mitral valve disease Mitral valve disease Aortic valve disease Mitral valve disease Dilative cardiomyopathy Aortic valve disease Mitral valve disease

All results are means -CSEM. No patient was affected by ischemic cardiomyopathy. BMI, Body mass index.

experimental findings, the present study was undertaken to investigate the possible metabolic and cardiovascular benefits of chronic @-adrenergic blockade in patients with chronic congestive heart failure. METHODS Patients. Ten patients with chronic congestive heart failure were studied. The diagnosis of chronic congestive heart failure was based on results of complete clinical examination and confirmed by instrumental analyses according to the method of Jafri et a1.i’ All patients were clinically stable but remained symptomatic despite the use of digitalis and furosemide throughout the study. They had been hospitalized previously to monitor cardiac function and to prevent an acute recurrence of the disease during the study; they had not been treated previously with thiazide diuretics and had hepatic and renal function that was at the upper limit of the normal range (as documented by routine laboratory tests). None of the patients had a family history of diabetes or obstructive lung disease, advanced atrioventricular block or active alcoholism, and all were on similar diets containing 250 gm of carbohydrates/day. After a complete explanation of the potential risks, all subjects gave informed consent to participate in the study, which was approved by the ethics committee of our institution. More detailed data concerning the patients are given in Table I. Experimental design. After a $-week stabilization and run-in period, all patients were assigned to receive either placebo or metoprolol in a double-blind, crossover, randomized manner. Patients were started on a regimen of 6.25 mg once daily and were then given 6.25 to 12.5 mg increments of placebo or metoprolol over a S-month period, with a therapeutic end point of 50 mglday to achieve a systolic blood pressure not lower than 90 mm Hg and a resting heart rate not less than 60 beats/min. All patients underwent clinical evaluation with each increase in dosage and were then observed for bradycardia, hypotension, or clinical decompensation for 2 hours after administration of the

drug. At the end of the run-in, placebo, and metoprolol periods all patients underwent metabolic and noninvasive cardiologic testing. A washout period of 4 weeks separated placebo from metoprolol administration. Metabolic studies. On all occasions patients were studied in the morning, starting at 8 or 9 AM, after a 12-hour overnight fast. They were kept in bed in the supine position throughout the entire experiment. On one day basal samples were drawn for determination of plasma counterregulatory hormone levels, and oral glucose tolerance tests (75 gm) were carried out. On another day a hyperinsulinemic glucose clamp test was performed. In the latter test an l&gauge polyethylene catheter was inserted into the antecubital vein of each arm and was used for all infusions; a superficial dorsal hand vein was cannulated in an anterograde manner with a 19-gauge butterfly needle and kept patent by slow infusion of saline solution. The hand was kept warm by a heated box for intermittent sampling of arterialized blood. During the 240 minutes of the test, regular human insulin (Humulin R, Eli Lilly and Company, Florence, Italy) was infused at two different rates (0.25 and 0.50 mU/kg/min) each lasting 120 minutes, while glucagon (Novo, Copenhagen, Denmark) was given at the fixed rate of 67 nglmin. To inhibit endogenous pancreas secretion, cyclic somatostatin (Modustatin, Midy-Sanofy, Milan, Italy) (4.5 rg/min) was infused over a period of 0 to 240 minutes. All three hormones, insulin, glucagon, and somatostatin, were dissolved in saline solution containing 0.3 gm/dl human serum albumin (Human Albumin, ISI, Milan, Italy). Along with insulin, variable amounts of glucose were infused according to the principles of the euglycemic glucose clamp technique described by De Fronzo et a1.13 Glucose was infused as a 20 % solution to which 0.26 mEq potassium chloride was added to prevent hypokalemia. To quantify the rate of hepatic (endogenous) glucose output and the overall glucose disappearance rate in the basal state and during glucose clamping, a primed (25 PCi), continuous (0.25 &i/min) infusion of D-3-H glucose (New England Nuclear, Boston, Mass.; specific activity 11.5 Ci/

Volume Number

123 1

Beta blockade in CHF

Plasma

Glucose 0.25

Plasma

2 566

426

E

‘-d 204 fi a

-

OL I

I

-30

0

1

I 60

5 ’ ; lg 8

Insulin

566

-

426

-

246

-

142

-

I

1

I

Fig. 1. Plasma glucose and insulin levels cose tolerance test after placebo (e) and administration. All results are means + Statistically significant differences were **p < 0.01.

0.50

‘~mln’

mU~kg’~mIn’

I

120

180 Time

mU,kg

o-

a I?

142

105

1200

-

(min)

during oral metoprolol SEM (n = *p < 0.05

glu(0) 10). and

e, 2

&. 6 1 i= ia

900 600 300

O-

mmol) dissolved in saline solution was used. At least 180 minutes were allowed for isotopic equilibration during which the various solutions were prepared. A high-precision pump (Hoechst, Frankfurt, Germany) was used to infuse the D-3-H glucose. Blood sampling. For measurements of glucose turnover, blood samples were collected at -30, -20, -15, -20, -5, and 0 minutes. Subsequently blood samples were collected every 20 minutes during the 240 minutes of the experiment. Blood samples for C-peptide, insulin, glucagon, growth hormone, and cortisol were collected in 10 ml heparinized tubes containing 0.9 ml of EDTA-Trasylol solution (Trasylol, Bayer, Germany; 5000 U/ml) and disodium-EDTA (I.2 mg/ml). Samples for determination of plasma glucose and glucose turnover parameters were collected in tubes containing a trace of sodium fluoride. Plasma samples for determination of catecholamine levels were collected as previously described.14 Analytic technique. Except for the plasma glucose level, which was determined immediately after the experiment by the glucose-oxidase method (Beckman Autoanalyzer, Beckman Instruments, Muenchen, Germany), all other blood samples for determination of hormone levels and glucose turnover parameters were centrifuged after each experiment and the plasma stored at -20’ C until assay.

I111111111,,,, 0 40

-30

so

120

160

200 Time

240 (min)

Fig. 2. Plasma glucose, insulin, glucagon, and C-peptide levels after placebo (0) and metoprolol(0) administration. All results are means rfr SEM (n = 10).

Plasma insulin, glucagon, C-peptide, cortisol, growth hormone, and FFA levels were all determined as reported elsewhere.i5 Glucose specific activity was also determined as previously reported.15 Plasma catecholamine levels were determined radioenzymatically.16 Plasma samples obtained from each subject were assayed within the same series to eliminate interassay variations. Cardiologic studies. During drug maintenance, patients were reevaluated every 2 weeks. The New York Heart Association (NYHA) guidelines were used for functional classification along with a questionnaire that was filled out at each visit and requested information regarding the patient’s ability to perform routine daily activities.17 Compliance was ensured by careful questioning and counting of tablets. Serial noninvasive testing included measurement of left ventricular radionuclide ejection fraction,18 bimodal

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Table II. Basal plasma glucoregulatory hormone ter placebo and metoprolol administration

0.50 mu. kg.‘.min‘

0.2 5 mu. kg”. min”

Hormone j Glucose

January 1992 Heart Journal

Disappearance

6-

Placebo

Plasma insulin (pmol/L)

107

Plasma

117 k 23

glucagon

p Value

levels afMetoprolol

NS

115 i- 21

NS

124

3.6 + 0.3

NS

3.8 -t 0.4

333.8 k 35.6

NS

339.6 + 41.7

358.4 + 58.7

NS

388.9 + 54.9

5.38 t 0.16

NS

5.11 + 0.38

t

18

+ 21

b-&L)

Plasma

growth

hormone

(fig/L) Plasma

cortisol

(nmol/L) Plasma

adrenaline

(pmol/L) Plasma norepinephrine (nmol/L)

~ Hepatic

I

0

I

I

40

I

I

80

I

I

120

I

I

160

Glucose

I

I

Output

I

200 Time

I

240 (min)

Fig. 3. Changes in glucose disappearance rate and hepatic glucose output after placebo (0) and metoprolol administration (0) during euglycemic hyperinsulinemic glucose clamp test. All results are means + SEM (n = 10). Statistically significant differences were *p < 0.05, **p < 0.03, and ***p < 0.01.

echocardiographic left ventricular end-diastolic determinations,lg and maximal oxygen consumption estimated by multistage exercise treadmill testing (MET score).2o The latter test was carried out according to a standard Naughton or Bruce protocol20r 21 by Burdick treadmill (ExTol700, Kone Instruments, Milton, Wise.) and evaluated according to the method of Engelmeir et a1.7 Data from all cardiologic tests were supervised and interpreted in a blinded manner by physicians not associated with the study. Functional classifications and management decisions were usually made by a blinded study physician who had not participated in the drug titration. Nevertheless, it should be pointed out that the metoprolol-induced bradycardiamight theoretically have opened the double-blind procedure, and consequently the increase in New York Heart Association functional class and exercise performance may at least in part have been influenced by physician bias. Calculations and statistical analysis. The rate of hepatic glucose output and the overall glucose disappearance rate were calculated from the isotopic data by means of the classic monocompartmental model of Steelez2 with the use

All results are means _t SEM. All determinations overnight fast (12 hours). No significant changes hormones were found in a comparison of run-in

were performed after in plasma glucoregulatory and placebo periods.

of 20-minute integrated values. This model is known to produce negative values for hepatic glucose output, which when present were taken to indicate nil hepatic glucose output and were not used further.23 Along the clamp hepatic glucose output was derived from the difference between the overall glucose appearance rate and the infusion rate of cold glucose. Total body glucose metabolism was calculated by adding the mean rate of hepatic glucose output (if the number was positive) during the last 60 minutes of the clamp procedure to the mean glucose infusion rate during the same period.23 After metoprolol administration the percentage decreases in basal plasma FFA levels and in hepatic glucose output, as well as the increase in the glucose disappearance rate, were calculated by considering the corresponding basal values as 100 % . Glucose and insulin areas under the curve were calculated as increments above baseline by the trapezoidal method.24 Comparisons of changes in NYHA functional class when subjects were switched from placebo to metoprolol were made by Friedman’s two-way analysis of variance. Comparisons of changes in MET score, ejection fraction, and left ventricular end-diastolic dimension and in the metabolic studies from placebo to metoprolol were made by two-tailed t tests for paired data. Heart responses to exercise at the end of the run-in, placebo, and metoprolol periods were evaluated for significance by covariance. Coefficient of correlation was calculated by means of the coefficient r of Pearson; p < 0.05 was chosen as the level of significance. All calculations and statistical analyses were carried out on an IBM computer with a SOLO software package (BMDP statistical software, Dublin, Ireland). All results are means + SEM. RESULTS Oral glucose

tolerance test. After loading with 75 gm of glucose (Fig. l), despite similar basal and postabsorptive

plasma

insulin

levels,

plasma

glucose

levels

Volume Number

123 1

f t* II11 Free Fatty

800 -

600-

400

-

0'

120’

-L

0

0

20

30

were lower after treatment with P-receptor antagonist. In particular, after 2 hours plasma glucose levels (8.2 * 0.3 vs 7.1 + 0.4 mmol/L, p < 0.05) were still significantly lower after ,&receptor blockade. Moreover, glucose (0.83 f 0.08 vs 0.71 + 0.11 mol/ L X min, p < 0.02) but not insulin (32.1 + 0.7 vs 31.2 f 0.9 PmollL X min, p = NS) areas under the curve were significantly lower after administration of metoprolol. When placebo and run-in periods were compared, no significant differences were found in any of the parameters reported previously. Hyperinsulinemic glucose clamp test. Basal plasma glucose and insulin levels were similar under both experimental conditions. After infusions were begun, plasma glucose levels (Fig. 2) were kept close to basal values and within a narrow range (coefficient of variation 3.4 +- 0.5 % vs 3.8 + 0.6%) p = NS) without significant differences in the two experimental conditions tested. Plasma insulin levels reached a stable plateau at approximately 147 and 349 pmol/L when insulin infusion rates were 0.25 and 0.50 mU/ kg x min, respectively. No significant differences in plasma insulin levels were detected in the absence or presence of metoprolol. Basal plasma C-peptide levels (918 f 111 vs 901 +- 133 pmol/L, p = NS) were strongly and similarly inhibited by somatostatin infusion, reaching extremely low values at the end of both tests. Plasma glucagonlevels, which were slightly

g

0

40

% INHIBITION

50

107

II

240’

4. Changesin plasmaFFA levels under basal conditions (0’) and at the end of each period of glucoseclamping (120’ and 240’, respectively) after placebo (I) and metoprolol (m ) administration. All results are mean i- SEM (n = 10). Statistically significant differences were **p < 0.01 and ***p < 0.005. Fig.

50

T

L

. z E a

Acids

Beta blockade in CHF

50

60

OF HGO

L

40 t

3a : E w

8 . I_ 0 00 0 0

30

z 3 g

20

;

10

I-

01

’

’

10

’

’

20

’

% INCREASE

’

30

’

’

40

’

’

50

IN Rd

Fig. 5. Correlation between percentage decrease in

plasmaFFA levels and percentageincreasein hepatic glucoseoutput (HGO) (top) (r = 0.66, p < 0.05) and decrease in glucose disappearancerate (Rd) (bottom) (r = 0.71, p < 0.05).

but not significantly higher (118 + 33 vs 133 f 21 rig/L) after administration of metoprolol, were similarly replaced at basal levels on both occasions, without any significant difference between the two experimental conditions. Basal hepatic glucose output (2.11 r 0.21 vs 1.87 f 0.27 mg/kg X min, p = NS) and glucose disappearance rates (2.01 -t 0.18 vs 2.12 & 0.31 mg/

108

Paolisso et al.

American

4o _

80

-

120

t

NYHA FC

MET SCORE

RNV EF

January 1092 Heart Journal

LVEDD

Fig. 6. Percentage improvement in NYHA functional class (FC), MET score, radionuclide left ventricular ejection fraction (RNVEF), and left ventricular end-diastolic dimension (LVEDD) after metoprolol (m) and placebo (I) administration. All results are means L SEM (n = 10). Statistically significant difference was *p < 0.05.

kg X min, p = NS) were not affected by administration of ,&receptor antagonist (Fig. 3). Insulin delivery promptly decreased hepatic glucose output and increased the glucose disappearance rate. Nonetheless, during metoprolol administration the extent of these insulin-mediated changes in glucose metabolism was significantly different, since we observed a stronger inhibition of hepatic glucose output and a remarkable stimulation of insulin-mediated glucose uptake. Total body glucose metabolism (3.97 + 0.13 vs 4.89 -t 0.22 mg/kg X min, p < 0.02) was also significantly enhanced after administration of metoprolol. All plasma glucose turnover parameters were similar when run-in and placebo periods were compared. Changes in plasma glucoregulatory FFA levels. There were no significant

hormones

and

changes in basal plasma glucoregulatory hormone concentrations after administration of metoprolol (Table II). p-Receptor blockade caused a significant decrease in basal plasma FFA levels (Fig. 4). Moreover, at the end of the two clamping periods (120 and 240 minutes), an insulin-mediated decrease in plasma FFA levels seemed to be potentiated by metoporolol administration. Furthermore, after administration of p-receptors the percentage decrease in basal plasma free fatty acid levels correlated significantly with percent-

age increase in insulin-mediated inhibition of hepatic glucose output and stimulation of the glucose disappearance rate (Fig. 5). Cardiovascular data. Resting heart rate and systolic blood pressure did not change with placebo and remained at 94 f 13 beats/min and 106 f 8 mm Hg, respectively. With metoprolol, however, resting heart rate and systolic blood pressure decreased significantly to 71 +- 8 beats/min (p < 0.001) and 97 & 4 mm Hg (p < 0.05), respectively. The mean heart rate and systolic blood pressure responses to exercise with placebo did not change from the run-in control values, but with metoprolol they were suppressed at all levels of exercise compared with placebo (all p < 0.01). As reported in Fig. 6, metoprolol administration does not significantly affect the cardiac index, radionuclide left ventricular ejection fraction, or left ventricular end-diastolic dimension. On the contrary, NYHA functional class and MET scores were slightly but significantly improved. Adverse effects. Patients received an average maintenance dose of 50 k 2 mg/day metoprolol. During the dosing phase, patients occasionally had weakness, fatigue, nausea, and mild worsening of symptoms of heart failure; nevertheless, none of the patients had to drop out of the study. Our protocol

Volume Number

123 1

of metoprolol administration and patient selection did not result in any serious exacerbation of heart failure or cardiovascular collapse. Metoprolol administration allowed a significant reduction in the mean dosage of furosemide (37.5 * 4.17 vs 29.5 +- 3.45 mglday, p < 0.05), whereas the dosage of digitalis remained practically unchanged. DISCUSSION

Among the compensatory mechanisms in the failing myocardium, an increase in plasma norepinephrine levels together with a concurrent overdrive of the adrenergic nervous system can occur.1-6 Such a pathophysiologic finding has been confirmed by Cohn et a1.,3 who demonstrated that in heart failure basal plasma norepinephrine levels are significantly raised, ranging from 400 to 1000 pg/ml, and are a guide to the prognosis. Such an increase in plasma norepinephrine levels has also been shown to be responsible for metabolic and cardiovascular disturbances. As far as the metabolic changes are concerned, previous reports lo, l1 have shown congestive heart failure to be an insulin-resistant state, mainly because of an increase in plasma FFA levels after the occurrence of exaggerated plasma norepinephrine levels. The increase in plasma FFA levels, by a mass action mechanism, may increase their own cellular uptake, thus stimulating lipid oxidation.25, 26 In muscle the accelerated rate of fat oxidation can inhibit insulin-mediated disposal of glucose, whereas in the liver it will stimulate gluconeogenesis and increase the hepatic glucose output.25s 26 From a cardiovascular standpoint, increased plasma norepinephrine levels allow (1) a positive inotropic effect through stimulation of myocardial p receptors, which leads to a secondary increase in intracellular cyclic adenosine monophosphate and greater calcium availability for myocardial contractile elements; (2) arterial and venoconstriction with an ensuing increase in preload and afterload; (3) secondary increase in plasma neurohormone (renin, angiotensin II, arginine, and vasopressin) levels.* Nevertheless, persistently high plasma norepinephrine levels may downregulate cardiac fl-adrenergic receptors with a consequent further increase in plasma norepinephrine secretion.69 27 Thus a vicious circle occurs between plasma norepinephrine and myocardial P-receptor levels. In light of such cardiovascular pathophysiologic findings, and to stop the vicious circle described above, P-adrenergic-blocking drugs have been introduced into the therapeutic protocol for congestive heart failure. Nevertheless, there have been no studies to investigate the metabolic consequences of a such /?-adrenergic blockade.

Beta blockade in CHF

109

Findings in the present study confirm previous data 7p8 which demonstrated the positive cardiovasculai therapeutic effects of /3-adrenergic-blocking agents in patients with congestive heart failure and initially showed that @-adrenergic blockade also has beneficial metabolic effects. In fact, metoprolol significantly improved insulin-mediated inhibition of hepatic glucose output and stimulation of glucose uptake. So far the metabolic effects of metoprolol administration might be explained by the close relationship that exists among P-receptor activity, intracellular metabolism of cyclic AMP, and glucose and lipid metabolism. In fact, stimulation of p receptors enhances intracellular cyclic AMP, which is a secondary messenger for the glycolenolysis at the liver site and lipolysis peripherally (mainly adipose cells)28-31; as a consequence ,B-adrenergic blockade remarkably reduces glycogenolysis and lipolysis, thus contributing to decreased plasma glucose levels and improved insulin sensitivity at the liver site and peripherally (muscle and adipose tissues). The inhibition of lipolysis further contributes to the improvement in insulin sensitivity despite elevated plasma catecholamine levels. In fact, metoprolol shields adipose cells from the exaggerated plasma noradrenalin levels, thus allowing a significant decrease in basal and insulinmediated plasma FFA levels; consequently hepatic neogluconeogenesis and muscular lipid oxidation are reduced. The key role of FFA levels in glucose homeostasis is supported by results of a previous study32 and is also indirectly strengthened by the occurrence in the present study of a significant correlation between the decrease in plasma FFA levels and the percentage changes in hepatic glucose output and in the glucose disappearance rate. The beneficial effects of metoprolol administration on glucose turnover parameters might be reversed by the inhibitory role that fl-adrenergic blockade has been shown to have on pancreatic beta cells.33 However, we have not found such data to be a likely consequence of the low dosage used. Furthermore, after P-adrenergic blockade patients were in a significantly lower NYHA class and had increased exercise capacity, even if there was no evidence of a progressive improvement in the resting radionuclide left ventricular ejection fraction and echocardiographic left ventricular end-diastolic dimension. To explain such data it has been suggested that long-term treatment with P-blockers is associated with upregulation of P-receptors, as well as improved catecholamine responsiveness,6, 8 even if it is still unclear whether such changes are important in mediating the benefits of P-blockade in these patients.6 In

110

Paolisso et al.

fact, the upregulated receptors remain pharmacologically blocked, and other p-blockers (i.e., xamoterol) may produce cardiovascular benefits without producing an increase in the density of P-receptors. On the other hand, when @receptors are pharmacologically shielded at plasma membrane levels, there is a decline in the production of cyclic AMP, the increase of which has been demonstrated to produce adverse clinical effects in patients with congestive heart failure.” Moreover, catecholamines per se seem to be cardiac toxins. In fact, patients with pheocromocytoma have a high incidence of cardiomyopathy, and the foci of necrosis can be demonstrated pathologically in such patients.8 Similarly cardiomyopathy can be induced in a variety of animals given infusions of norepinephrine, and foci of necrosis have been demonstrated in the myocardium of patients with normal hearts who were given pharmacologic doses of catecholamines8 Thus @-blockers may also protect against this catecholamine-induced cardiac toxic effect. In conclusion, our study demonstrated that metopro101 is a useful therapeutic agent in the treatment of congestive heart failure, since it allows a concurrent improvement in the metabolic and cardiovascular parameters disturbed by long-term exposure to exaggerated plasma catecholamine levels. REFERENCES

1. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978;41:233-43. 2. Levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn JN. Activity of the sympathetic nervous system and renin angiotensin system assessed by plasma hormone levels and their relationship to hemodynamic abnormalities in congestive heart failure. Am 3 Cardiol 1982;49:1659-66. V, Lura D, Francis 3. Cohn JN, Levine TB, Olivari MT, Garberg GS, Simon AR, Rector T. Plasma norepinephrine as guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819-23. 4. Bristow MR. The adrenergic nervous system in heart failure. N Engl J Med 1984;311:850-1. 5. Pierpont GL, Francis GS, De Master EG, Olivari MT, Ring WS, Goldenberg IF, Reynolds S, Cohn IN. Heterogeneous myocardial catecholamine concentrations in patients with conaestive heart failure. Am J Cardiol 1987;60:316-21. 6. Packer M. Neurohormonal indications and adaptations in congestive heart failure. Circulation 1988;77:721-30. 7. Englemeir RS, O’Connel I, Walsh R, Rod N, Sconlon P, Gunnar RM. Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a doubleblind. randomized, placebo-controlled trial. Circulation 1985;72:536-46. or irrational therapy for 8. Shanes JG. B-blockade-rational congestive heart failure? Circulation 1987;76:971-3. M, Nie Z, Goeztz G, Henriksson J, Walleberg-Hen9. Bostrom riksson H. Indirect effect of catecholamines on development of insulin resistance in skeletal muscle from diabetic rats. Diabetes 1989;38:906-10. 10. Paolisso G, De Riu S, Marrazzo G, Verza M, Varricchio M, D’Onofrio F. Insulin resistance in chronic congestive heart

American

11.

12.

13.

14.

15.

16.

17.

18.

19. 20.

21.

22. 23.

24.

25. 26. 27.

28.

29. 30.

31.

32.

33.

January 1992 Heart Journal

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