stress test to evaluate adrenergic beta

STRESS TEST TO EVALUATE ADRENERGIC BETABLOCKADE IN MITRAL VALVE PROLAPSE PATIENTS SOME RELATED CLINICAL AND BIOLOGIC FEATURES
Emília P. Silva, MD, Lena Neves, MD, Manuel P. Bicho, MD, Ana R. Victor, MD, J. A. Correia
Cunha, MD, and Mário G. Lopes, MD
University Hospital Santa Maria, Cardiology Department. Faculty Medicine, Medicina I. Centro
Cardiologia Universidade Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
e-mail:[email protected]
Abstract: Fatigue and exercise intolerance are
common complaints in mitral valve prolapse (MVP)
patients (pts), even with normal systolic ventricular
function and without significant mitral regurgitation.
Although not clarified, their pathogenesis has been
suggested to be mediated by high levels of
catecholamines.
Adrenergic beta-blockers antagonize the effects of
catecholamines. To our knowledge, their role in the
exercise tolerance of these patients has never been
studied.
The aim of this controlled study was to evaluate the
results of long term adrenergic beta blockade with
propranolol in the effort capacity of MVP patients with
normal systolic ventricular function and with no or mild
mitral regurgitation, using exercise stress test in
cicloergometer.
In conclusion, medication ameliorated symptoms and
improved exercise tolerance in these patients.
INTRODUCTION:
Even with normal ventricular function, patients
with mitral valve prolapse often complain of effort
intolerance.
Although identical to normal for exercise
performed in supine position, the exercise
tolerance of MVP patients has been demonstrated
to be lower when sitting or standing.1-3 Cardiac
output and left ventricular late diastolic volume, in
these pts, diminish during stress in standing but
remain normal during stress in decubitus.2,3 These
phenomena have been attributed to chronic
vasoconstrition
and
inherent
diminished
1
intravascular volume and pre-load. MVP patients
often have high levels of norepinephrine which
produces vasoconstriction through stimulation of
α1 and α2 adrenergic receptors.4-10
Adrenergic beta-blockers antagonize the effects of
catecholamines.
For the above reasons, we designed a study to
evaluate the role of long term adrenergic beta
blockade with propranolol in symptomatic patients
with MVP and high levels of norepinephrine.
MATERIAL AND METHODS:
Population.
Normal Group - 39 normal individuals, 18 men
(mean age 44.61±15.28 years) and 20 women
(mean age 45.71±11.95 years). Patients Group –
51 symptomatic (fatigue and exercise intolerance)
MVP patients free of medications, 20 men (mean
age 44.05±14.74 years) and 31 women (mean age
45.00±12.83 years).
The diagnosis of mitral valve prolapse was based
upon clinical and echocardiographic criteria: 42
pts had both a midsystolic click and a late systolic
murmur; 9 pts had isolated midsystolic click.
Murmur and click varied appropriately in timing
and intensity with physical manoeuvers during
auscultation (decubitus, sitting, standing and
squatting positions).
Two-dimensional echocardiography in the
parasternal long-axis view displayed systolic
billowing of both mitral leaflets across the mitral
anulus in 29 pts, and systolic billowing of the
posterior leaflet alone in 22 pts.
Color-flow Doppler echocardiography assessment
of severity of mitral regurgitation, based on jet
length, documented 1+ in 36 pts, and 2+ in 4 pts.
There was no mitral regurgitation in 11 pts.
Mean left atrial dimension was 34.2±2.3 mm;
mean left ventricular diastolic dimension was
46.1±3.7 mm; mean left ventricular systolic
dimension was 27.8±3.1 mm; fractional shortening
was 38.6±4.3%.
Methods.
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A-Normal individuals and patients were submitted
to:
1) 1.a)-Determination of 24 hours urinary
epinephrine (E) and norepinephrine (NE)
levels using high performance liquid
cromatography (HPLC).
1.b)-Determination of creatinine urinary levels
by the Jaffé method.
2) Maximal stress test (basal) in cicloergometer
according to a modified Astrand protocol:
continuous stress with initial charge of 30
watts, additional increments of 30 watts every
3 minutes, and continuous speed of 60
rotations/minute.
B-Patients underwent a second stress test (β block)
after 10 to 12 (mean 10.82) months under oral
propranolol 10 mg t.i.d..
MVP Patients (Basal) versus MVP Patients (ß block)
MVP (basal) MVP(ß block)
7.31±1.27
p<0.001
Female 5.39±1.40
11.21±1.97
12.93±2.29
p<0.01
Male
Exercise tolerance improved significantly in MVP
patients under long term beta-adrenergic blockade,
in relation to MVP patients without medication.
Table IV. EXERCISE TOLERANCE (minutes)
Normal versus MVP Patients (ß block)
Normal
Female 8.05±2.05
13.59±3.38
Male
MVP(ß block)
7.31±1.27
NS
12.93±2.29
NS
minutes
14
12
RESULTS.
The results of catecholamines, in ng/mg creatinine,
are shown in Table I.
Table I. URINARY CATECHOLAMINES
(ng/mg creatinine)
Normal
MVP
11.21±9.16 p<0.001
E Female 6.12±3.49
Male 5.12±2.48
8.86±3.87 p<0.01
NE Female 28.09±7.36 49.01±23.97 p<0.001
Male 22.19±7.25 37.17±17.88 p<0.01
E-epinephrine; NE- norepinephrine
The levels of both epinephrine and norepinephrine
were significantly higher in patients when
compared to normal people.
The results of exercise tolerance, in minutes, are
shown in Tables II, III, IV and Figure 1.
Table II. EXERCISE TOLERANCE (minutes)
Normal versus MVP Patients (Basal)
Normal
MVP (basal)
p<0.0001
Female 8.05±2.05 5.39±1.40
13.59±3.38 11.21±1.97
p<0.01
Male
When compared to normal individuals, exercise
tolerance was significantly lower in MVP patients
without medication, both women and men.
Table III. EXERCISE TOLERANCE (minutes)
10
8
normal
6
basal
4
β block
2
0
Male
Female
Figure 1. Exercise tolerance for gender in normal,
patients (basal) and patients (β
β block)
Compared to basal ones, MVP patients under
propranolol had higher exercise tolerance, that was
not significantly different from that of normal
people.
While taking propranolol, patients were less
symptomatic.
DISCUSSION.
Fatigue and exercise intolerance in MVP patients,
although not clarified, has been suggested to be
mediated by high levels of catecholamines.
Determination of urinary levels of catecholamines
is a reliable method for evaluation of the
sympathetic activity. The patients of our study had
high levels of epinephrine and norepinephrine as
did those studied by other authors.4-10
Effort capacity was significantly lower in patients
free of medication than in normal individuals. This
557
as already been demonstrated in other studies
when exercise was performed while sitting , as it
was in our study, or standing. These phenomena
have been attributed to chronic vasoconstrition and
inherent diminished intravascular volume and preload.1 Norepinephrine produces vasoconstrition
through stimulation of α1 and α2 adrenergic
receptors.
Adrenergic beta-blockers antagonize the effects of
catecholamines and decrease the norepinephrine
release at postganglionic sympathetic nerve
endings.
In our study, we evaluated the role of chronic
adrenergic beta-blockade on the effort capacity of
these patients. To our knowledge, there are no
published studies on this item.
Under chronic adrenergic beta-blockade with
propranolol, patients were less symptomatic;
exercise tolerance improved markedly and became
not significantly different from that of normal
people. These results suggest the role of
catecholamines in the genesis of fatigue and
exercise intolerance in these patients
5.
6.
7.
8.
9.
CONCLUSIONS.
Symptomatic MVP patients, when compared to
normal
people, had higher
levels
of
catecholamines. and lower exercise tolerance.
Long term beta-blockade ameliorated symptoms
and improved effort capacity up to close to
normal.
References:
1. Gaffney F A, Bastian B C, Lane L B, Taylor
W F, Horton J. Abnormal cardiovascular
regulation in the mitral valve prolapse
syndrome. Am J Cardiol 1983;52:316-20
2. Coghlan H C, Carranza C, Hsiung M C,
Alliende I. Abnormal left ventricular volume
response during upright exercise in
symptomatic
mitral prolapse
patients.
(Abstract) X World Congr Cardiol 1986;
Abstract Book:120
3. Bashore T M, Grines C L, Utlak D, Boudoulas
H, Wooley C F. Postural exercise
abnormalities in symptomatic patients with
mitral valve prolapse. J Am Coll Cardiol
1988;11:499-507
4. Boudoulas H, Wooley C F, Reynolds J C,
Mazzaferri E. Mitral valve prolapse syndrome
10.
– evidence for a hyper-adrenergic state
(Abstract). Am J Cardiol 1979;43:368
Pasternac A, Tubau J F, Puddu P E, Król R B,
Champlain J. Increased plasma catecholamine
levels in patients with symptomatic mitral
valve prolapse. Am J Med 1982;73:783-90
Boudoulas H, Reynolds J C, Mazzaferri E,
Wooley C F. Mitral valve prolapse syndrome:
the effect of adrenergic stimulation. J Am Coll
Cardiol 1983;2:638-44
Coghlan H C. Autonomic dysfunction in the
mitral valve prolapse syndrome: the brainheart connection and interaction. In:
Boudoulas H, Wooley C F (eds). Mitral Valve
Prolapse and the Mitral Valve Prolapse
Syndrome. Mount Kisco, New York, Futura
Publishing Company. Inc. 1988:389-426
Micieli G, Cavallini A, Melzi d’Eril G V,
Tassorelli C, Barzizza F, Verri A P, Richichi I,
Nappi G: Haemodynamic and neurohormonal
responsiveness to different stress tests in
mitral valve prolapse. Clin Autonomic Res
1991;1:323-7
Davies A O, Mares A, Pool J L, Taylor A A.
Mitral valve prolapse with symptoms of betaadrenergic hypersensitivity. Beta 2-adrenergic
receptor supercoupling with desensitization on
Isoproterenol exposure. Am J Med
1987;82:193-201
Boudoulas H, Reynolds J C, Mazzaferri E,
Wooley C F. Metabolic studies in mitral valve
prolapse syndrome: a neuroendocrinecardiovascular process. Circulation 1980;
61:1200-5
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