Endocrine Predictors of Acute Hemodynamic Effects of Growth Hormone in CHF

	August 20, 1999 - Our study involved 12 chronic CHF patients, all
male. Ten patients were in Class 3-4 and two were in Class 2. The first
24 hours were the control period. During the following 24 hours, all
patients took constant IV recombinant human GH (Growth Hormone).
	Blood samples were taken every 20 minutes during the first night
and at 8 AM each of the 3 days of the study. Pulmonary artery pressure
(PAP) and capillary wedge (PCWP) pressure, cardiac index, and arterial
blood pressure were measured 30 minutes after right heart cath, at the
end of the control period, and every 4 hours during infusion.
	Conclusions: Growth Hormone has acute effects on heart function
in CHF patients, including an increase in the heart's ability to squeeze
and a decrease in vascular resistance. Among CHF patients, those with low
baseline IGF-1 will likely get less benefit from GH.

Long version:

	Growth hormone (GH) is involved in many body processes, either
directly or through its mediator: insulin-like growth factor-1 (IGF-1).
It has long been known that GH has structural effects on the left ventricle.
	GH may play a role in regulating heart structure and function. In
fact, giving extra GH causes the heart to contract with much greater than
usual force in healthy people. Recombinant human GH, given for 3 months in
patients with idiopathic DCM and CHF, increases heart mass and reduces left
ventricle volume, improving blood flow.
	Short-term continuous IV of recombinant human GH in 12 men with
severe CHF increased average cardiac index by 50%. After 24 hours of GH
infusion, there was also a 25% drop in pulmonary artery pressure.

Patients

	The study's 12 male patients all had stable CHF, an average EF of
21%, therapy with digoxin, diuretics, and vasodilators; an average peak
exercise oxygen consumption of 10mL/kg per minute; and no arrhythmia. We
did not include patients taking alpha-blockers or beta-blockers.

Protocol

	All patients entered the study after a 7 day stabilization period
in a hospital. The first 24 hours after right heart cath were considered
the control period. During the following 24 hours, all the patients took
constant IV infusion of 0.1IU/kg per 24 hours of recombinant human GH.
Patients were continuously monitored during the 48 hours of the study.
	Standard medical therapy for heart failure was continued
unchanged throughout the study. Meals, which were standardized for each
patient (9 MJ/day, 15% protein, 50% carbohydrates and 35% lipids) were
served at 7 AM, noon, and 6 PM of each day. No extra calories were allowed.

Procedures

	Heart chamber dimensions, left ventricular thickness and functional
systolic indexes were done by echo. A bicycle exercise test was done,
consisting of a 3-minute warm up period at no resistance followed by
step-ups of 10 watts every minute. Gases were analyzed with a mass
spectrometer. The exercise test was stopped when patients complained of
either severe shortness of breath or fatigue.
	Right heart cath was done the morning of the first study day, after
patients had fasted overnight and had received their usual oral therapy.
Pulmonary artery pressure (PAP) and pulmonary capillary pressure (PCWP) were
measured. Cardiac output and arterial blood pressure were measured. All
these were also measured 30 minutes after right heart cath, at the end of
the control period, and every 4 hours during GH infusion.
	During GH infusion, blood samples were drawn at baseline and at 2
and 4 hours after the beginning of the infusion, then every 4 hours until
the end of the infusion. The same amount of 0.1 IU/kg body weight per 24
hours of biosynthetic recombinant human GH was given through constant
continuous IV to all patients. Cardiac index was figured as cardiac
output/body surface area (L/min/m2).

Results

	The average patient night-time GH level was 2.5mg/L. Peak GH level
was 8.6mg/L. Average GH blood level increased during infusion 5 times higher
than baseline from 2.5 to 13.6mg/L). IGF-1 rose about 50% compared with
baseline from 169 to 248mg/L. Average GH levels during the infusion ranged
from 3.4 to 33.1mg/L. IGF-1 levels after GH infusion ranged from 130 to
404mg/L.
	Baseline hemodynamic tests showed impaired left ventricular
performance in all patients. In fact, average cardiac index was 2L/min/m2.
Average PAP was 40mm Hg. Data consistent with pulmonary hypertension
(average PAP greater than 20mm Hg) were noticed in all but one patient.
Systemic and pulmonary vascular resistance was elevated in all subjects.
	* In the systemic circulation, after 24-hour continuous GH infusion,
we found a dramatic (50% over baseline) increase in average cardiac index
vs baseline levels (3.3 vs 2.1L/min/m2). * The cardiac index increase after
infusion ranged between 10% and 200% vs baseline. We found no differences in
heart rate and systolic arterial pressure, but we saw a significant decrease
in diastolic and average arterial pressure. Systemic resistance fell
significantly in all patients.
	In pulmonary circulation, after 24-hour continuous GH infusion, an
important (25% less than baseline) drop in hemodynamic measures was seen. A
decrease in systolic PAP (47 vs 60mm Hg), diastolic PAP (21 vs 27), and PCWP
(18 vs 24mm Hg) was seen. Average PAP decrease after infusion ranged from
7 to 50% vs baseline.

Discussion

	Short-term (24-hour) continuous IV infusion of recombinant human
GH can dramatically improve both left and right ventricle performance,
resulting in a dramatic increase in cardiac index (by 50% over baseline
levels) and a reduction in pulmonary arterial pressure (approximately 25%)
in patients with severe CHF. Consequently, our interest was in endocrine
predictors of these GH effects in CHF patients to better select candidates
for this treatment.
	Spontaneous GH hypersecretion or hyposecretion have been related
to heart dysfunction. The data suggest that the pituitary could have a role
in the endocrine compensatory response to heart failure. We looked at
possible effects of an acute but sustained elevation of circulating GH
levels - obtained through 24-hour IV infusion - on heart function in patients
with severe CHF.

	Our data show that GH was able to increase cardiac index over the
short term. This was not only impressive on an average basis (50% improvement
vs baseline) but we saw a normalization of this measure in most patients
studied. The increase in cardiac output was accompanied by a decrease in
pulmonary pressures that was only slightly less impressive than the effect
on cardiac index (average decrease of 25%). These effects occurred along with
a decrease in systemic and pulmonary resistance.
	On the basis of these data, it can be hypothesized that GH has very
prominent functional effects on the heart. It is likely that GH may increase
heart contractility and reduce vascular resistance.
	All the hemodynamic effects of GH were seen soon (4 to 8 hours) after
beginning the infusion and continued to improve (cardiac index) throughout
the study. The mechanism by which GH increases myocardial contractility is
unclear. Our data show for the first time that the effects of GH on cardiac
performance are independent of the mechanism of cardiac hypertrophy.
	In the current study, giving GH caused significant elevations in
both circulating GH and IGF-1 levels. IGF-1 has been shown to increase the
contractility of rats' heart cells. In vivo studies have also shown that
IGF-1 treatment enhances cardiac output and stroke volume in rats with CHF.
	Interestingly, the effects of GH were hardly dependent on baseline
hemodynamics. However, the baseline endocrine picture of the patients seemed
to relate to how well they responded to GH. In fact, patients with low
circulating IGF-1 levels and high GH levels (those characterized by a
certain degree of "GH resistance") were likely to have less dramatic increase
in IGF-1 and hemodynamic responses.
	If, in the clinical setting, low baseline circulating IGF-1 levels
are a good predictor of a weak hemodynamic response to GH infusion, one
would expect that we will be able to find the cutoff IGF-1 level under which
giving GH has no significant effect.
	We conclude that GH has acute functional effects on the heart in CHF
patients. Among patients with CHF, those with low baseline IGF-1 are likely
to get less benefit from GH. Perhaps peripheral GH resistance impairs
cardiovascular response to GH infusion according to impaired liver function
or cardiac production of IGF-1 or an impaired GH action at cardiac level.
Data suggest that all the studies on the cardiovascular effect of GH need to
be designed by carefully considering the baseline endocrine picture of the
patients.
	
	Finally, inotropic treatments so far tested in CHF patients are
catecholaminergic drugs that stimulate the ehart to squeeze harder (dopamine
and dobutamine) and non-catecholaminergic drugs (amrinone, milirone and
enoximone - phosphodiesterase inhibitors) with vasodilating effects.
	Our study was not designed to compare GH use to these drugs. However,
the acute hemodynamic effects of GH seem comparable to them. On the basis of
our data, comparative trials need to be done to find the possible place of
GH among the so-called "inotropic drugs" in the short-term treatment of CHF.

Am Heart J 137(6):1035-1043, 1999