Categories:
Appetite suppressants
Epoprostenol (Flolan), Nitric Oxide
Prognosis
Biochemistry & Genetics
Anticoagulation
Echocardiography
Liver Disease
New Therapies
Transplantation
Appetite
suppressants
Am J
Cardiol 2000 Apr 1;85(7):913-5, A10
Chronic
treatment with phentermine combined with fenfluramine lowers plasma
serotonin.
Rothman
RB, Redmon JB, Raatz SK, Kwong CA, Swanson JE, Bantle JP
rbrothman@aol.com
As
expected on the basis of published research in both humans and animals,
treatment
with phentermine/fenfluramine lowers plasma 5-hydroxytryptophan,
whereas
treatment with phentermine had no significant effect. In light of these
findings,
future research should focus on mechanisms other than increased plasma
5-hydroxytryptophan
to explain how fenfluramine increases the risk of primary
pulmonary
hypertension and valvular heart disease.
Chest
2000 Mar;117(3):870-4
Anorexigens
and pulmonary hypertension in the United States: results from the
surveillance
of North American pulmonary hypertension.
Rich S,
Rubin L, Walker AM, Schneeweiss S, Abenhaim L
Section
of Cardiology, Rush Medical College, Chicago, IL 60612-3824,
srich@rush.edu
BACKGROUND:
The use of appetite suppressants in Europe has been associated with
the
development of primary pulmonary hypertension (PPH). Recently, fenfluramine
appetite
suppressants became widely used in the United States but were withdrawn
in
September 1997 because of concerns over adverse effects. MATERIALS AND
METHODS:
We conducted a prospective surveillance study on patients diagnosed
with
pulmonary hypertension at 12 large referral centers in North America. Data
collected
on patients seen from September 1, 1996, to December 31, 1997,
included
the cause of the pulmonary hypertension and its severity. Patients with
no
identifiable cause of pulmonary hypertension were classed as PPH. A history
of drug
exposure also was taken with special attention on the use of
antidepressants,
anorexigens, and amphetamines. RESULTS: Five hundred
seventy-nine
patients were studied, 205 with PPH and 374 with pulmonary
hypertension
from other causes (secondary pulmonary hypertension [SPH]). The use
of
anorexigens was common in both groups. However, of the medications surveyed,
only
the fenfluramines had a significant preferential association with PPH as
compared
with SPH (adjusted odds ratio for use > 6 months, 7.5; 95% confidence
interval,
1.7 to 32.4). The association was stronger with longer duration of use
when
compared to shorter duration of use and was more pronounced in recent users
than in
remote users. An unexpectedly high (11.4%) number of patients with SPH
had
used anorexigens. CONCLUSION: The magnitude of the association with PPH, the
increase
of association with increasing duration of use, and the specificity for
fenfluramines
are consistent with previous studies indicating that fenfluramines
are
causally related to PPH. The high prevalence of anorexigen use in patients
with
SPH also raises the possibility that these drugs precipitate pulmonary
hypertension
in patients with underlying conditions associated with SPH.
Epoprostenol
(Flolan), Nitric Oxide
Heart
2000 Apr;83(4):406-9
Treatment
with epoprostenol reverts nitric oxide non-responsiveness in patients
with
primary pulmonary hypertension.
Ziesche
R, Petkov V, Wittmann K, Kopatschka J, Stiebellehner L, Schenk P,
Germann
P, Roder G, Ullrich R, Block LH
Department
of Internal Medicine IV, University of Vienna Medical School,
Wahringer
Gurtel 18-20, A-1090 Vienna, Austria.
OBJECTIVE:
To assess whether long term treatment with epoprostenol might restore
primary
non-responsiveness to nitric oxide (NO) in patients with primary
pulmonary
hypertension. METHODS: Seven patients with primary pulmonary
hypertension
receiving intravenous epoprostenol continuously because of failure
of NO
to influence pulmonary haemodynamics during initial testing were followed
over a
period of 13-29 months. Afterwards, acute vascular reactivity towards NO
was
tested again during right heart catheterisation. RESULTS: Administration of
NO
after continuous epoprostenol treatment for a mean period of 18 months
improved
arterial oxygen saturation (p < 0.01) and cardiac index (p < 0.05), and
decreased
mean pulmonary artery pressure (p < 0.01) and total pulmonary vascular
resistance
(p < 0.01) in patients previously unresponsive to NO. CONCLUSIONS:
Long
term treatment with epoprostenol reverts initial refractoriness to NO in
patients
with primary pulmonary hypertension. Thus the addition of NO to
epoprostenol
treatment might cause further improvement in the course of the
disease.
J Am
Coll Cardiol 2000 Jan;35(1):176-82
A
comparison of the acute hemodynamic effects of inhaled nitric oxide and
aerosolized
iloprost in primary pulmonary hypertension. German PPH study group.
Hoeper
MM, Olschewski H, Ghofrani HA, Wilkens H, Winkler J, Borst MM,
Niedermeyer
J, Fabel H, Seeger W
Department
of Pulmonary Medicine, Hannover Medical School, Germany.
KMHoeper@AOL.com
OBJECTIVE:
We sought to compare the acute hemodynamic effects of inhaled nitric
oxide
(NO) and aerosolized iloprost in primary pulmonary hypertension (PPH).
BACKGROUND:
Inhalation of the stable prostacyclin analogue iloprost has recently
been
described as a novel therapeutic strategy for PPH and may offer an
alternative
to continuous intravenous infusion of prostacyclin or inhalation of
NO.
METHODS: During right heart catheterization, 35 patients with PPH
sequentially
inhaled 40 ppm of NO and 14 to 17 microg of iloprost, and the
effects
on hemodynamics and blood gases were monitored. RESULTS: Both NO and
iloprost
caused significant increases in cardiac output, mixed-venous oxygen
saturation
and stroke volume as well as significant decreases in pulmonary
artery
pressure and pulmonary vascular resistance, whereas only inhaled iloprost
significantly
increased the arterial PO2 (p = 0.01). Compared with inhaled NO,
aerosolized
iloprost was more effective in reducing pulmonary artery pressure
(-8.3
+/- 7.5 mm Hg vs. -4.3 +/- 8.8 mm Hg; p = 0.0001) and the pulmonary
vascular
resistance (-447 +/- 340 dynes x s x cm(-5) vs. -183 +/- 305 dyne x s x
cm(-5);
p < 0.0001). Furthermore, aerosolized iloprost caused a significantly
greater
increase of the cardiac output compared with NO (+0.7 +/- 0.6 liter/min
vs.
+0.3 +/- 0.4 liter/min; p = 0.0002) and had a more pronounced effect on the
mixed-venous
oxygen saturation (p = 0.003). CONCLUSIONS: During acute drug
testing,
aerosolized iloprost was more potent than inhaled NO as a pulmonary
vasodilator
in PPH at the doses used in this study.
Chest
2000 Jan;117(1):14-8
Epoprostenol
for treatment of pulmonary hypertension in patients with systemic
lupus
erythematosus.
Robbins
IM, Gaine SP, Schilz R, Tapson VF, Rubin LJ, Loyd JE
Center
for Lung Research, Department of Medicine (Drs. Robbins and Loyd),
Vanderbilt
University School of Medicine, Nashville, TN 37232, USA.
Ivan.Robbins@mcmail.vanderbilt.edu
OBJECTIVE:
Pulmonary hypertension with pathological changes similar to those
observed
in primary pulmonary hypertension occurs in patients with systemic
lupus
erythematosus (SLE). The efficacy of chronic epoprostenol therapy in SLE
has not
been well described. The objective of this paper is to describe our
experience
with long-term epoprostenol therapy in patients with pulmonary
hypertension
associated with SLE. DESIGN: Case series of six patients with SLE
and
associated pulmonary hypertension receiving chronic treatment with
epoprostenol.
RESULTS: All 6 patients had severe pulmonary hypertension. Mean
pulmonary
artery pressure (mPAP) was 57 +/- 9 mm Hg (mean +/- SD), and pulmonary
vascular
resistance was 14 +/- 7 units before beginning therapy with
epoprostenol.
In 4 patients who underwent repeat hemodynamic evaluation (9 to 16
months
after starting epoprostenol), mean pulmonary artery pressure decreased by
38 +/-
21% and pulmonary vascular resistance by 58 +/- 12%. Clinically, all
patients
improved from New York Heart Association class III or IV to class I or
II.
Doses of epoprostenol ranged from 4 to 46 ng/kg/min, and the longest
duration
of therapy has been 2.5 years. Side effects from epoprostenol have not
differed
from those seen in patients with primary pulmonary hypertension, and
except
for one patient, there has been no exacerbation of SLE. CONCLUSION:
Epoprostenol
was effective for the treatment of pulmonary hypertension in this
small
group of patients with SLE. Further evaluation of epoprostenol therapy for
patients
with SLE and other diseases associated with pulmonary hypertension is
warranted.
Chest
1999 Oct;116(4):914-20
Effects
of long-term infusion of prostacyclin on exercise performance in
patients
with primary pulmonary hypertension.
Wax D,
Garofano R, Barst RJ
Division
of Pediatric Cardiology, Columbia University College of Physicians and
Surgeons,
New York, NY. d-wax@nwu.edu
STUDY
OBJECTIVES: To determine whether long-term IV prostacyclin (PGI(2)) use
improves
exercise capacity in patients with primary pulmonary hypertension
(PPH).
DESIGN: Cycle ergometry and the 6-min walk was used to evaluate the
exercise
performance of patients with PPH. The patients underwent serial
exercise
testing after starting continuous IV PGI(2) and were followed up for
19.5
+/- 7.5 months. Peak work, peak oxygen consumption (f1.gif"
BORDER="0">O(2)),
peak O(2) pulse, and distance walked in 6 min were used to
evaluate
performance. BACKGROUND: PPH is characterized by medial hypertrophy and
intimal
proliferation of the pulmonary arterioles, leading to elevation of
pulmonary
artery pressure, right ventricular failure, and death. Palliative
treatment
consists of vasodilators, anticoagulants, cardiac glycosides,
diuretics,
and transplantation. PGI(2), a potent vasodilator and inhibitor of
platelet
aggregation, has been used for long-term treatment when conventional
therapy
has been unsuccessful. PATIENTS: Sixteen patients with PPH (10 women, 6
men;
mean age, 24 years). RESULTS: At the initiation of PGI(2), peak work (+/-
SD) was
35.5 +/- 11% of predicted; peak f1.gif" BORDER="0">O(2), 39
+/- 10.4%;
peak
O(2) pulse, 5.0 +/- 1.7 mL/min; and distance on the 6-min walk, 428 +/- 78
feet.
At 18 to 27 months, peak work increased to 58.8 +/- 23% of predicted (p =
0.001),
peak f1.gif" BORDER="0">O(2) increased to 52 +/- 15% of
predicted (p =
0. 02),
peak O(2) pulse increased to 7.1 +/- 3.0 mL/beat (p = 0.004), and
performance
on the 6-min walk increased to 526 +/- 62 feet (p = 0.001). There
was a
positive correlation between peak f1.gif" BORDER="0">O(2) and
peak 6-min
walk of
0.6 (p < 0.005) and between peak work and peak 6-min walk of 0.6 (p <
0.005).
CONCLUSIONS: Exercise capacity improved in our patients at up to 27
months
of follow-up. Exercise testing is helpful in assessing the functional
capacity
of patients with PPH and may be useful in guiding therapy. Patients who
deteriorate
while receiving optimal conventional therapy should be considered
for IV
PGI(2) therapy.
J Am
Coll Cardiol 1999 Oct;34(4):1184-7
The
effects of chronic prostacyclin therapy on cardiac output and symptoms in
primary
pulmonary hypertension.
Rich S,
McLaughlin VV
Department
of Medicine, Rush University Medical College, Chicago, Illinois, USA.
srich@rush.edu
OBJECTIVES:
This study evaluated the response to prostacyclin dose reduction in
patients
with primary pulmonary hypertension (PPH) who developed high cardiac
outputs.
BACKGROUND: Patients on prostacyclin require chronic upward dose
titration
to overcome tolerance to the medication. No upper limit of effective
dose
has been described. METHODS: We studied 12 patients with PPH treated with
chronic
prostacyclin therapy who presented in high cardiac output states. Each
patient
underwent prostacyclin dose reduction under hemodynamic guidance
targeted
to reduce the cardiac index to < or =4 liter/min/M2, unless rebound
pulmonary
hypertension occurred. Following dose reduction, patients were
observed
for changes in the effectiveness of the prostacyclin. RESULTS: Patients
were
treated for 39 +/- 20 months, resulting in a 71% reduction in pulmonary
vascular
resistance compared to baseline. At the time of their most recent
evaluation
their cardiac outputs were increased to 10.1 +/- 2.3 liter/min. The
patients
underwent a 39% dose reduction (range 12% to 78%) resulting in a change
of mean
PAP from 45 to 46 mm Hg (p = NS), cardiac index from 7.4 +/- 1.4 to 4
+/-
0.74 liter/min/M2 (p = 0.01), and pulmonary vascular resistance from 3.7 +/-
1.7 to
4.7 +/- 1.5 units (p < 0.001). In no instance did rebound pulmonary
hypertension
occur. However, the patients all retained their clinical benefit
without
a return of tolerance. CONCLUSIONS: Excessive prostacyclin in PPH can
lead to
a high cardiac output state, suggesting it has important positive
inotropic
effects. In this circumstance, reducing the dose can allow the cardiac
output
to return to normal without worsening the clinical state.
Prognosis
Chest
2000 Mar;117(3):796-800
Mortality
from primary pulmonary hypertension in the United States, 1979-1996.
Lilienfeld
DE, Rubin LJ
Department
of Medicine, School of Medicine (Dr. Rubin), University of California
at San
Diego, USA. David.Lilienfeld@bms.com
STUDY
OBJECTIVES: To determine whether primary pulmonary hypertension mortality
in the
United States increased since 1979 coincident with the introduction of
anorexigens.
DESIGN: Examination of annual age-adjusted and age-specific primary
pulmonary
hypertension mortality in the United States from 1979 through 1996 and
in five
selected states from 1992 through 1996. SETTING: The United States, from
1979
through 1996. PATIENTS OR PARTICIPANTS: Residents of the United States,
from
1979 through 1996. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Annual
age-adjusted
mortality increased at different rates among white men and women
and
black men and women. The greatest increase was among black women (who also
had the
highest rates). Age-specific mortality showed a high rate among infants
< 1
year old, a low rate in childhood, and an ascending rate throughout the
remainder
of life. Similar patterns were identified at the state level.
CONCLUSIONS:
Primary pulmonary hypertension mortality in the United States has
increased
notably since 1979. Some portion of this increase may be related to
the
introduction of anorexigens. Improvements in diagnostic recognition may also
explain
part of the increase in mortality. These results need to be confirmed in
a
diagnosis validation study, particularly because the same mortality data
suggest
that the disease may be more common in the elderly than has been
previously
reported.
Am J
Respir Crit Care Med 2000 Feb 1;161(2 Pt 1):487-492
Clinical
Correlates and Prognostic Significance of Six-minute Walk Test in
Patients
with Primary Pulmonary Hypertension. Comparison with cardiopulmonary
exercise
testing.
Miyamoto
S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N,
Miyatake
K
Division
of Cardiology, Department of Medicine, National Cardiovascular Center,
Osaka;
and College of Medical Technology, Kyoto University, Kyoto, Japan.
The
six-minute walk test is a submaximal exercise test that can be performed
even by
a patient with heart failure not tolerating maximal exercise testing. To
elucidate
the clinical significance and prognostic value of the six-minute walk
test in
patients with primary pulmonary hypertension (PPH), we sought (1) to
assess
the relation between distance walked during the six-minute walk test and
exercise
capacity determined by maximal cardiopulmonary exercise testing, and
(2) to
investigate the prognostic value of the six-minute walk test in
comparison
with other noninvasive parameters. The six-minute walk test was
performed
in 43 patients with PPH, together with echocardiography, right heart
catheterization,
and measurement of plasma epinephrine and norepinephrine.
Symptom-limited
cardiopulmonary exercise testing was performed in a subsample of
patients
(n = 27). Distance walked in 6 min was significantly shorter in
patients
with PPH than in age- and sex-matched healthy subjects (297 +/- 188
versus
655 +/- 91 m, p < 0.001). The distance significantly decreased in
proportion
to the severity of New York Heart Association functional class. The
distance
walked correlated modestly with baseline cardiac output (r = 0.48, p <
0.05)
and total pulmonary resistance (r = -0.49, p < 0.05), but not
significantly
with mean pulmonary arterial pressure. In contrast, the distance
walked
correlated strongly with peak V O(2) (r = 0.70, p < 0.001), oxygen pulse
(r =
0.57, p < 0.01), and V E-VCO(2) slope (r = -0.66, p < 0.001) determined
by
cardiopulmonary
exercise testing. During a mean follow-up period of 21 +/- 16
mo, 12
patients died of cardiopulmonary causes. Among noninvasive parameters
including
clinical, echocardiographic, and neurohumoral parameters, only the
distance
walked in 6 min was independently related to mortality in PPH by
multivariate
analysis. Patients walking < 332 m had a significantly lower
survival
rate than those walking farther, assessed by Kaplan-Meier survival
curves
(log-rank test, p < 0.01). These results suggest that the six-minute walk
test, a
submaximal exercise test, reflects exercise capacity determined by
maximal
cardiopulmonary exercise testing in patients with PPH, and it is the
distance
walked in 6 min that has a strong, independent association with
mortality.
Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M,
Nakanishi
N, Miyatake K. Clinical correlates and prognostic significance of
six-minute
walk test in patients with primary pulmonary hypertension: comparison
with
cardiopulmonary exercise testing.
J Am
Coll Cardiol 1997;30:343-9
Primary
Pulmonary Hypertension: Improved Long-Term Effects and Survival With Continuous
Intravenous Epoprostenol Infusion
Shelley
M. Shapiro, MD, PhD, FACC, Ronald J. Oudiz, MD, Tiesheng Cao, MD, Matthew A.
Romano, BA, X. Joy Beckmann, Demitrios Georgiou, MD, FACC, Sarathy Mandayam,
MD, Leonard E. Ginzton, MD, FACC, Bruce H.
Brundage,
MD, FACC
Torrance,
Los Angeles, Long Beach and Loma Linda, California; Xi'an, People's Republic of
China; and New York, New York.
Objectives.
This study sought to determine the long-term effects of continuous infusion of
epoprostenol (epo) therapy on survival and pulmonary artery pressure in
patients with primary pulmonary hypertension (PPH).
Background.
PPH is a progressive disease for which there are few effective therapies. Methods. Patients with PPH and New York Heart
Association functional class III or IV symptoms of congestive heart failure
underwent
right heart catheterization and Doppler-echocardiography to measure the maximal
systolic pressure gradient between the right ventricle and right atrium (P) and
cardiac output (CO). Doppler-echocardiography and catheterization data were
compared. Patients were followed up long term with Doppler-echocardiography.
Results.
Of 69 patients who went on to receive epo, 18 were followed up for >330 days
(range 330 to 700). During long-term follow-up, there was a significant
reduction in P, which decreased from 84.1 ± 24.1 to 62.7 ± 18.2 (mean ± SD, p <
0.01). A Kaplan-Meier plot of survival of our study patients demonstrated
improved survival compared with that of historical control subjects. The 1-, 2-
and 3-year survival rates for our patients were 80% (n = 36), 76% (n = 22) and
49% (n = 6) compared with 10- (88%, n = 31), 20- (56%, n = 27) and 30-month
(47%, n = 17) survival rates in historical control subjects. Conclusions.
Patients receiving continuous infusion of epo for treatment of PPH experience a
decrease in pulmonary artery
pressure.
Long-term follow-up of this single-center patient group demonstrated improved
long-term survival during epo therapy compared with that in historical control
subjects and confirms predicted improved outcomes based on shorter follow-up periods.
Biochemistry
& Genetics
Am J
Respir Crit Care Med 2000 Mar;161(3 Pt 1):1055-9
Fine
mapping of PPH1, a gene for familial primary pulmonary hypertension, to a
3-cM
region on chromosome 2q33.
Deng Z,
Haghighi F, Helleby L, Vanterpool K, Horn EM, Barst RJ, Hodge SE, Morse
JH,
Knowles JA
Departments
of Genetics and Development, Medicine, Pediatrics, and Psychiatry,
and
Columbia Genome Center, College of Physicians and Surgeons, Columbia
University;
Division of Biostatistics, School of Public Health, Columbia
University;
and New Yo.
Familial
primary pulmonary hypertension (PPH) is a rare autosomal dominant
disease
characterized by distinctive changes in pulmonary arterioles that lead
to
increased pulmonary artery pressures, right ventricular failure, and death.
Our
previous studies had mapped the disease locus, PPH1, to a 27-cM region on
chromosome
2q31-q33, with a maximum multipoint logarithm of the odds favoring
genetic
linkage score of 3.87 with markers D2S350 and D2S364. To narrow the
minimal
genetic region for PPH, we physically mapped 33 highly polymorphic
microsatellite
markers and used them to genotype 44 affected individuals and 133
unaffected
individuals from 17 families with PPH. We observed recombination
events
that substantially reduced the interval for PPH1 to the approximately
3-cM
region that separates D2S311 and D2S1384. This entire region lies within
chromosome
2q33. A maximum two-point lod score of 7.23 at a recombination
fraction
of zero was obtained for marker D2S307. A maximum multipoint lod score
of 7.41
was observed close to marker D2S1367. The current minimal genetic region
contains
multiple candidate genes for PPH, including a locus thought to play a
role in
lung cancer. Deng Z, Haghighi F, Helleby L, Vanterpool K, Horn EM, Barst
RJ,
Hodge SE, Morse JH, Knowles JA. Fine mapping of PPH1, a gene for familial
primary
pulmonary hypertension, to a 3-cM region on chromosome 2q33.
Cardiovasc
Res 1999 Nov;44(2):274-82
Role
of endothelial and smooth muscle cells in the physiopathology and treatment
management
of pulmonary hypertension.
Veyssier-Belot
C, Cacoub P
Service
de Medecine Interne, CHI Poissy-Saint Germain, France.
Pulmonary
hypertension can occur either as primary or secondary disease
following
cardiac or pulmonary illnesses. In either cases, histological lung
biopsies
reveal vascular remodelling i.e. smooth muscle cells proliferation with
medial hypertrophy,
arteriolar muscularization and endothelial cell
proliferation.
Subsequent intimal thickening, fibrosis and in situ thrombosis,
altogether
lead to vaso-occlusive alterations referred to as plexiform lesions.
Theories
concerning the detailed physiopathology of pulmonary hypertension have
focused
on endothelial and smooth muscle cells' chemical factors production and
response
to different mediators. The endothelium produces vasoconstrictor and
growth-promoting
factor such as endothelin-1 (ET-1) as well as vasodilator and
growth-inhibitor
factors like prostacyclin and nitric oxide (NO). ET-1 has been
noted
in high concentrations in some clinical cases and experimental models of
pulmonary
hypertension, coupled with ET-1 receptors' modulation and altered
endothelin
converting enzyme activities, suggesting their active role in both
arteriolar
vasoconstriction and occlusion. Vascular thrombosis which has been
noted
by pathologists in pulmonary hypertension, could be related to an
imbalance
between thrombotic inducing factors (such as anti-phospholipid
antibodies,
ET-1 and thromboxane) and decreased fibrinolytic activity and
antiaggregant
endothelial factors (like prostacyclin, NO, thrombomodulin). The
discovery
of an endothelial cells' monoclonal proliferation in plexiform lesions
of
patients with primary pulmonary hypertension may reinforce the cellular
proliferation
hypothesis to understand the histopathology of this disease. In
view of
these new findings, the treatments available for pulmonary hypertension
have
been expanded from the previously employed oxygen therapy, calcium-channel
blockers
and anticoagulants, to intravenous prostacyclin analogues
(epoprostenol)
and inhaled nitric oxide.
Circulation
1999 Jun 29;99(25):3266-71
Continuous
infusion of epoprostenol improves the net balance between pulmonary
endothelin-1
clearance and release in primary pulmonary hypertension.
Langleben
D, Barst RJ, Badesch D, Groves BM, Tapson VF, Murali S, Bourge RC,
Ettinger
N, Shalit E, Clayton LM, Jobsis MM, Blackburn SD, Crow JW, Stewart DJ,
Long W
Division
of Cardiology, Sir Mortimer B. Davis Jewish General Hospital, Montreal,
Canada.
mddl@musica.mcgill.ca
BACKGROUND:
Primary pulmonary hypertension results from progressive narrowing of
the
precapillary pulmonary vasculature. A variety of endothelial abnormalities
have
been identified, including a net reduction in pulmonary clearance of the
vasoconstrictor
and smooth muscle mitogen endothelin-1. In many patients, net
pulmonary
release of endothelin-1 is observed. Chronic infusions of epoprostenol
(prostacyclin)
improve functional capacity, survival, and hemodynamics in
patients
with advanced primary pulmonary hypertension. We hypothesized that the
epoprostenol
infusions, as compared with conventional therapy, might alter the
abnormal
pulmonary endothelin-1 homeostasis. METHODS AND RESULTS: Using a subset
of
patients from a larger randomized study comparing epoprostenol plus
conventional
therapy (n=11 in the present study) with conventional therapy alone
(n=7 in
the present study), we determined the ratio of plasma endothelin-1
levels
in systemic arterial blood leaving the lung to levels in mixed venous
blood
entering the lung both before randomization and after 88 days of
continuous
therapy. There were no differences between the 2 groups before
therapy,
but by day 88, the epoprostenol-treated group had a greater proportion
of
patients (82%) with an arterial/venous ratio <1 than did the conventional
therapy
group, in which only 29% of patients had a ratio <1 (P<0.05).
CONCLUSIONS:
These results suggest that continuous epoprostenol therapy may have
a
beneficial effect on the balance between endothelin-1 clearance and release in
many
patients with primary pulmonary hypertension and may provide one
explanation
for the salutary effect of epoprostenol in this disease.
Anticoagulation
J Lab
Clin Med 1999 Dec;134(6):561-6
Prothrombotic
mechanisms in primary pulmonary hypertension.
Farber
HW, Loscalzo J
Whitaker
Cardiovascular Institute, Pulmonary Center, Boston University School of
Medicine,
MA 02118, USA.
Pulmonary
hypertensive states are associated with an increased propensity for
thrombosis.
This prothrombotic state appears to be a result of pulmonary
hypertension
promoting endothelial dysfunction and altered hemodynamic status.
In some
patients with primary pulmonary hypertension, however, a primary
prothrombotic
state directly induces the pulmonary hypertensive state. This
review
focuses on the evidence for the association between prothrombotic states,
especially
increased platelet activation, and the development of pulmonary
hypertension.
Echocardiography
Chest
1999 Nov;116(5):1218-23
Echocardiographic
predictors of an adverse response to a nifedipine trial in
primary
pulmonary hypertension: diminished left ventricular size and leftward
ventricular
septal bowing.
Ricciardi
MJ, Bossone E, Bach DS, Armstrong WF, Rubenfire M
Division
of Cardiology, Department of Internal Medicine, University of Michigan
Medical
Center, Ann Arbor, MI, USA.
BACKGROUND:
The clinical course in primary pulmonary hypertension (PPH) is
improved
by calcium channel blocker therapy in those with a favorable
hemodynamic
response during a trial of high-dose oral nifedipine. Although
trials
of nifedipine are performed only in patients who demonstrate pulmonary
vasodilator
reserve to short-acting agents, this response does not predict the
safety
of nifedipine treatment, which can result in severe first-dose
hypotension
and death. Study objectives: To identify echocardiographic
parameters
that predict first-dose nifedipine-induced hypotension in patients
with
PPH. METHODS: The pretrial echocardiograms of 23 consecutive PPH patients
(mean
age, 42.3 +/- 13 years; 77% female) undergoing evaluation of pulmonary
vasodilator
reserve with nifedipine were analyzed. Patients were classified as
those
who suffered first-dose nifedipine hypotension (group 1) and those who did
not
(group 2). Echocardiographic measures of chamber size and septal geometry in
the two
groups were compared. RESULTS: Five measures reflecting diminished left
ventricular
(LV) size and leftward ventricular septal bowing were found to be
associated
with nifedipine hypotension: LV transverse diameter in systole (LVDs;
p =
0.007), LV transverse diameter in diastole (LVDd; p = 0.05), LV area in
systole
(LVAs; p = 0.009), LV area in diastole (LVAd; p = 0.03), the ratio of RV
to LVAs
(p = 0. 02), and leftward ventricular septal bowing (p = 0.01). The LV
dimensions
found to best predict nifedipine-induced hypotension were LVDs < 2.7
cm,
LVDd < 4.0 cm, LVAs < 15.5 cm(2), and LVAd < 20.0 cm(2). CONCLUSIONS:
Readily
available echocardiographic parameters in patients with PPH are
predictive
of nifedipine-induced hypotension, and can be used to select patients
in whom
a trial of nifedipine should be avoided.
J Am
Soc Echocardiogr 1999 Aug;12(8):655-62
Echocardiographic
features of primary pulmonary hypertension.
Bossone
E, Duong-Wagner TH, Paciocco G, Oral H, Ricciardi M, Bach DS, Rubenfire
M,
Armstrong WF
Division
of Cardiology, Department of Internal Medicine, University of Michigan,
Ann
Arbor, USA.
Primary
pulmonary hypertension (PPH) is essentially a diagnosis of exclusion and
usually
is made late because of the nonspecific nature of the early signs and
symptoms.
Echocardiography is a key screening test in the diagnostic algorithm
of
patients with suspected PPH. The purpose of this study was to define the
echocardiographic
Doppler features in patients with PPH at the time of
diagnosis.
From 1992 to 1997, 51 patients were diagnosed with PPH at our
institution.
All underwent a standardized transthoracic echocardiographic
examination,
including a contrast study and transthoracic echocardiographic
examination
if indicated. Pulmonary artery systolic pressure was calculated from
the
tricuspid regurgitation jet. The majority of patients had pulmonary artery
systolic
pressure greater than 60 mm Hg (96%) associated with systolic
flattening
of the interventricular septum (90%), enlarged right atrium (92%) and
ventricle
(98%), and reduced right ventricular systolic function (76%). There
was an
increase in the interventricular septal thickness (>1.2 cm) in 21 (43%)
of 49
patients, accompanied by a septal/posterior wall ratio greater than 1.3 in
11
(22%) of 49. Although a reduction in both left ventricular systolic and
diastolic
volumes was noted, global left ventricular systolic function was
preserved
in all patients. Mitral E/A ratio was less than 0.7 in 7 (22%)
patients
studied. Color Doppler revealed moderate to severe tricuspid
regurgitation
and pulmonic insufficiency in 41 (80%) of 51 and 16 (31%) of 51 of
cases,
respectively. Pericardial effusion (7 small and 1 moderate) and patent
foramen
ovale (n = 12) were also frequently detected. At the time of initial
diagnosis,
PPH is associated with secondary cardiac abnormalities in the
majority
of patients.
Liver
Disease
Indian
J Gastroenterol 1999 Oct-Nov;18(4):158-60
Primary
pulmonary hypertension in cirrhosis of liver.
Sen S,
Biswas PK, Biswas J, Das TK, De BK
Department
of Medicine, Institute of Post Graduate Medical Education and
Research,
Calcutta.
BACKGROUND:
Primary pulmonary hypertension (PPH) is a grave association of
portal
hypertension, and is potentially fatal in liver transplant candidates.
AIM: To
investigate the prevalence of PPH among cirrhotics with portal
hypertension.
METHODS: 43 cirrhotics with portal hypertension (Child B 22, C
14),
after screening for cardiopulmonary diseases, were evaluated by hemodynamic
study.
RESULTS: PPH was detected in 2 cases (4.7%), both in Child B, hepatitis B
and C
viruses being the etiologies. Neither had portal axis thrombosis. Two
other cases
also had pulmonary hypertension, but with high pulmonary capillary
wedge
pressure (PCWP). The 41 cases without and 2 cases with PPH had,
respectively,
mean pulmonary artery pressure (MPAP) 16.3 (5.9) mmHg, 26 mmHg and
33
mmHg; PCWP 11.5 (6.7) mmHg, 12 mmHg and 11 mmHg; transpulmonary pressure
gradient
4.8 (2.6) mmHg (n = 27), 14 mmHg and 22 mmHg; and pulmonary vascular
resistance
80.2 (55.8) dyne.sec.cm-5 (n = 27), 155.6 dyne.sec.cm-5 and 366.7
dyne.sec.cm-5.
No correlation of MPAP was found with either Child-Pugh scoring
(r2 =
0.0347) or with hepatic venous pressure gradient (r2 = 0.0021).
CONCLUSION:
PPH has a prevalence of 4.7% among cirrhotics with portal
hypertension;
it bears no relation with severity of liver disease.
New
Therapies
Ann
Intern Med 2000 Mar 21;132(6):435-43
Inhaled
iloprost to treat severe pulmonary hypertension. An uncontrolled trial.
German
PPH Study Group.
Olschewski
H, Ghofrani HA, Schmehl T, Winkler J, Wilkens H, Hoper MM, Behr J,
Kleber
FX, Seeger W
Department
of Internal Medicine II, Justus-Liebig-University, Giessen, Germany.
BACKGROUND:
Inhaled aerosolized iloprost, a stable prostacyclin analogue, has
been
considered a selective pulmonary vasodilator in the management of pulmonary
hypertension.
OBJECTIVE: To assess the efficacy of inhaled iloprost in the
treatment
of life-threatening pulmonary hypertension. DESIGN: Open,
uncontrolled,
multicenter study. SETTING: Intensive care units and pulmonary
hypertension
clinics at six university hospitals in Germany. PATIENTS: 19
patients
who had progressive right-heart failure despite receiving maximum
conventional
therapy (12 with primary pulmonary hypertension, 3 with pulmonary
hypertension
related to collagen vascular disease without lung fibrosis, and 4
with
secondary pulmonary hypertension). INTERVENTION: Inhaled iloprost, 6 to 12
times
daily (50 to 200 microg/d). MEASUREMENTS: Right-heart catheterization and
distance
walked in 6 minutes at baseline and after 3 months of therapy. RESULTS:
During
the first 3 months of therapy, New York Heart Association functional
class
improved in 8 patients and was unchanged in 7 patients. Four patients
died, 3
of right-heart failure and 1 of sepsis. The acute hemodynamic response
to
inhaled iloprost was predominant pulmonary vasodilatation with little
systemic
effect at baseline and at 3 months (data available for 12 patients).
Hemodynamic
variables were improved at 3 months, and the distance walked in 6
minutes
improved by 148 m (95% CI, 4.5 to 282 m; P = 0.048). Of the 15 patients
who
continued to use inhaled iloprost, 8 stopped: Four had lung transplantation,
1
switched to intravenous prostacyclin therapy, and 3 died. Seven patients are
still
receiving inhaled iloprost (mean +/-SD) duration of therapy, 536 +/- 309
days;
mean dosage, 164 +/- 38 microg/d). CONCLUSIONS: Inhaled iloprost may offer
a new
therapeutic option for improvement of hemodynamics and physical function
in
patients with life-threatening pulmonary hypertension and progressive
right-heart
failure that is refractory to conventional therapy.
J Am
Coll Cardiol 1999 Oct;34(4):1188-92
Effect
of orally active prostacyclin analogue on survival of outpatients with
primary
pulmonary hypertension.
Nagaya
N, Uematsu M, Okano Y, Satoh T, Kyotani S, Sakamaki F, Nakanishi N,
Miyatake
K, Kunieda T
Department
of Medicine, National Cardiovascular Center, Suita, Osaka, Japan.
OBJECTIVES:
This study sought to investigate the effect of beraprost sodium
(BPS),
an orally active prostacyclin analogue, on the survival of outpatients
with
primary pulmonary hypertension (PPH). BACKGROUND: Continuous intravenous
administration
of epoprostenol (prostacyclin) has been shown to improve survival
in PPH.
However, the effect of oral BPS on survival in PPH remains unknown.
METHODS:
Fifty-eight consecutive patients with PPH who could be discharged after
the
first diagnostic catheterization for PPH were retrospectively divided into
two
groups: patients treated with BPS (BPS group, n = 24) and those without BPS
(conventional
group, n = 34). The baseline demographic and hemodynamic data did
not
significantly differ between the two. RESULTS: Twenty-seven patients died of
cardiopulmonary
causes in the conventional group during a mean follow-up period
of 44
+/- 45 months. In contrast, only 4 patients died of cardiopulmonary causes
in the
BPS group during a mean follow-up period of 30 +/- 20 months. In a
subsample
(n = 15) of patients in the BPS group, mean pulmonary arterial
pressure
and total pulmonary resistance significantly decreased, respectively,
by 13%
and 25% during a mean follow-up period of 53 days. Among the variables
previously
known to be associated with the mortality in PPH, the absence of BPS
therapy
and the reduced cardiac output were independently related to the
mortality
by a multivariate Cox proportional hazards regression analysis (both p
<
0.05). The Kaplan-Meier survival curves demonstrated that the one-, two- and
three-year
survival rates for the BPS group were 96%, 86% and 76%, respectively,
as
compared with 77%, 47% and 44%, respectively, in the conventional group
(log-rank
test, p < 0.05). CONCLUSIONS: The oral administration of BPS may have
beneficial
effects on the survival of outpatients with PPH as compared with
conventional
therapy alone.
Transplantation
Ann
Thorac Surg 1999 Apr;67(4):937-41; discussion 941-2
Heart-lung
transplantation for primary pulmonary hypertension.
Whyte
RI, Robbins RC, Altinger J, Barlow CW, Doyle R, Theodore J, Reitz BA
Department
of Cardiothoracic Surgery, Stanford University, California 94305,
USA.
riwhyte@leland.stanford.edu
BACKGROUND:
The operation of choice for primary pulmonary hypertension remains
controversial,
as heart-lung transplantation, single-lung transplantation, and
double-lung
transplantation have all been advocated. METHODS: We reviewed our
institution's
experience with heart-lung transplantation for primary pulmonary
hypertension.
RESULTS: Thirty-nine patients had heart-lung transplantation for
primary
pulmonary hypertension. Operative mortality rate was 18%, and actuarial
survival
was 72% at 1 year, 67% at 2 years, and 42% at 5 years. Freedom from
obliterative
bronchiolitis was 91% at 1 year, 83% at 2 years, and 70% at 5
years.
Freedom from obliterative bronchiolitis-related death was 100% at 1 year,
90% at
2 years, and 87% at 5 years. Freedom from accelerated graft coronary
disease
was 92% at 5 years. The most frequent causes of death were infection,
obliterative
bronchiolitis, and accelerated graft coronary disease. CONCLUSIONS:
Heart-lung
transplantation results in survival comparable to that reported for
single
or double lung transplantation. Obliterative bronchiolitis is a
significant
cause of late death but seems to occur less frequently with
heart-lung
transplantation than with lung transplantation alone. Accelerated
coronary
graft disease is rare in the first 5 years after transplantation.