The investigators evaluated the safety and
effectiveness of sildenafil (Viagra), alone and in combination with
inhaled iloprost, for treatment of pulmonary hypertension. 30 patients
with severe pulmonary arterial hypertension (n = 16), chronic
thromboembolic pulmonary hypertension (n = 13), or pulmonary hypertension
due to aplasia of the left pulmonary artery (n = 1), all classified as New
York Heart Association class III or IV were then randomized to receive
12.5 mg of oral sildenafil, 50 mg of sildenafil, 12.5 mg of sildenafil
plus inhaled iloprost, or 50 mg of sildenafil plus inhaled iloprost.
The study showed in rank order of pulmonary
vasodilatory potency (maximum reduction of pulmonary vascular resistance
and increase in cardiac index), 50 mg of sildenafil plus iloprost was most
effective, followed by 12.5 mg of sildenafil plus iloprost. Iloprost alone
and 50 mg of sildenafil were almost equally effective but were less potent
than the combination regimens. In patients who received 50 mg of
sildenafil plus iloprost, the maximum change in pulmonary vasodilatory
potency was -44.2% (95% CI, -49.5% to -38.8%). compared with -14.1% (CI,
-19.1% to -9.2%) in response to nitric oxide.
Although limited by the small sample and lack of long-term data, the
study concluded that oral sildenafil is a potent pulmonary vasodilator
that acts synergistically with inhaled iloprost to cause strong pulmonary
vasodilatation in both severe pulmonary arterial hypertension and chronic
thromboembolic pulmonary hypertension. Furthermore, this combination
therapy may become a novel approach for the treatment of pulmonary
hypertension.
Bostenthan is an orally administered
dual endothelin-receptor antagonist that was shown
in a preliminary study to improve exercise capacity
and cardiopulmonary hemodynamics in patients with
pulmonary arterial hypertension. Ribin et al investigated
the effect of bosentan on exercise capacity in
a large number of patients and compared two doses.
In a double-blind, placebo-controlled
study, 213 patients with pulmonary arterial hypertension
(primary or associated with connective-tissue
disease) were randomly assigned to receive placebo
or 62.5 mg of bosentan twice daily for 4 weeks
followed by either of two doses of bosentan (125
or 250 mg twice daily) for a minimum of 12 weeks.
The primary end point of the study was the degree
of change in exercise capacity. Secondary end
points included the change in the Borg dyspnea
index, the change in the World Health Organization
(WHO) functional class, and the time to clinical
worsening. At week 16, patients treated with bosentan
had an improved six-minute walking distance; the
mean difference between the placebo group and
the combined bosentan groups was 44 m (95 percent
confidence interval, 21 to 67; P<0.001). Bosentan
also improved the Borg dyspnea index and WHO functional
class and increased the time to clinical worsening.
The study comcluded that bosentan
is beneficial in patients with pulmonary arterial
hypertension and is well tolerated at a dose of
125 mg twice daily. Endothelin-receptor antagonism
with oral bosentan is an effective approach to
therapy for pulmonary arterial hypertension.
(New Eng J Med. 2002;346:896-903)
Experimental data suggest that
long-chain n-3 polyunsaturated fatty acids found
in fish have antiarrhythmic properties, and a
randomized trial suggested that dietary supplements
of n-3 fatty acids may reduce the risk of sudden
death among survivors of myocardial infarction.
Whether long-chain n-3 fatty acids are also associated
with the risk of sudden death in those without
a history of cardiovascular disease is unknown.
Albert and colleagues conducted
a prospective, nested case-control analysis among
apparently healthy men who were followed for up
to 17 years in the Physicians’ Health Study. The
fatty-acid composition of previously collected
blood was analyzed by gas-liquid chromatography
for 94 men in whom sudden death occurred as the
first manifestation of cardiovascular disease
and for 184 controls matched with them for age
and smoking status.
The study found that baseline
blood levels of long-chain n-3 fatty acids were
inversely related to the risk of sudden death
both before adjustment for potential confounders
(P for trend = 0.004) and after such adjustment
(P for trend = 0.007). As compared with men whose
blood levels of long-chain n-3 fatty acids were
in the lowest quartile, the relative risk of sudden
death was significantly lower among men with levels
in the third quartile (adjusted relative risk,
0.28; 95 percent confidence interval, 0.09 to
0.87) and the fourth quartile (adjusted relative
risk, 0.19; 95 percent confidence interval, 0.05
to 0.71).
The study concludes that n-3 fatty acids found
in fish are strongly associated with a reduced
risk of sudden death among men without evidence
of prior cardiovascular disease.
(New Eng J Med. 2002;346:896-903)
It has been shown that antiproliferative
drugs such as paclitaxel lower the amount of intimal
hyperplasia after stent implantation in de-novo
lesions. Whether they are also beneficial in in-stent
restenosis is unknown. 15 consecutive patients
with elective indication to percutaneous coronary
intervention for in-stent restenosis were treated
with the QuaDS-QP2 stent implantation. At 6 months,
3 patients had target lesion revascularization
(20%). Two patients had restenosis (13.3%); one
experienced restenosis in a gap between 2 drug-eluting
stents, and the other had stent occlusion leading
to NQWMI. At 12 months, 1 patient suffered from
NQWMI, and 8 of 13 patients (61.5%) had angiographic
restenosis (late loss=1.36±0.94 mm with a loss
index=0.62±0.44).
The study concluded that this first experience
with QuaDS-QP2 stent implantation for in-stent
restenosis revealed minimal intimal hyperplasia
at the 6-month follow-up. However, the antiproliferative
effect was not maintained at the 12-month follow-up,
resulting in delayed occurrence of angiographic
restenosis.
(Circulation. 2002;105:1883-1886)
Using the prospective, multicenter
Coronary Artery Risk Development In Young Adults
(CARDIA) study, investigators examined the
10-year cumulative incidence of insulin resistance
syndrome (IRS) relative to dairy consumption as
estimated by diet history interviews.
A total of 3157 black and white
adults between the ages of 18 and 30 at baseline
were included in the study and followed for an
average of 10 years. Pereira and colleagues report
that milk and milk drinks were the most commonly
consumed dairy products, followed by butter, cream,
and cheeses. Generally, whites were more likely
to consume more dairy products than blacks, and
women consumed more dairy than men. When dairy
consumption was used to stratify study participants,
the authors found that overweight people who ate
35 or more servings of dairy products per week
were 72% less likely to develop IRS than people
who ate less than 10 servings of dairy products
per week. Of note, the inverse association between
dairy intake and IRS was observed in overweight,
but not leaner, participants. Fiber and protein
intake were also associated with IRS, although
neither confounded the association between dairy
and IRS. The authors also noted inverse associations
between dairy consumption and development of obesity,
abnormal glucose homeostasis, elevated blood pressure,
and dyslipidemia in overweight young adults, regardless
of race.
The study demonstrated that young, overweight
adults who consume high amounts of dairy products
have a reduced risk of developing insulin resistance
syndrome (IRS), a precursor to type 2 diabetes
and cardiovascular disease (CVD) . Pereira et
al point out that just as rates of diabetes and
CVD have escalated over the past 3 decades, dairy
consumption has declined, particularly in young
people who now turn to sugary soft drinks rather
than a glass of milk. While factors such as smoking
and low physical activity are known to promote
insulin resistance, the impact of diet is poorly
understood.
(JAMA 2002;287:2081-2089)
Recently Mukherjee D et al analyzed
the risk cardiovascular events associated with
selective COX-2 inhibitors , by reviewing data
from the two major trials VIGOR and CLASS and
demonstrated significantly higher risk of myocardial
infarction when compared to placebo.
The study of Cheng et al, in
mice could help shed light on why COX-2 inhibitors
might increase the risk of thrombotic events.
COX-1, the form of cyclooxygenase found in
platelets, makes TxA2, which causes blood vessels
to constrict and platelets aggregate - an early
step in clot formation. COX-2, by contrast, is
expressed in blood vessels and is a major source
of PGI2, which dilates blood vessels and prevents
the activation of platelets.
The investigators inflicted injury
on the carotid artery with a catheter in animals
bred to lack receptors for PGI2. They showed that
both the vascular response and the corresponding
activation of platelets were both markedly exaggerated.
Similarly, mice that over expressed receptors
for TxA2 also produced these exaggerated effects.
The effect was diminished when researchers either
deleted the TxA2 receptor or blocked the receptor
using an experimental drug. When the researchers
deleted both the TxA2 receptor and the PGI2 receptor,
it cancelled out the effect of inactivating the
PGI2 receptor alone.
(Science 2002; 296(5567):539 – 541)
CARDIOVASCULAR
