European Journal of Heart Failure 2008 10(5):463-466; doi:10.1016/j.ejheart.2008.03.010
© 2008 European Society of Cardiology
Effect of atorvastatin on plasma levels of asymmetric dimethylarginine in patients with non-ischaemic heart failure
Joanna M. Younga,*,
Christopher H. Streya,1,
Peter M. Georgeb,
Christopher M. Florkowskia,b,
Christiaan W. Siesb,
Christopher M. Framptonc and
Russell S. Scotta
a Lipid and Diabetes Research Group, Christchurch Hospital Christchurch, New Zealand
b Clinical Biochemistry Unit, Canterbury Health Laboratories Christchurch, New Zealand
c Department of Medicine, University of Otago Christchurch, New Zealand
* Corresponding author. Lipid & Diabetes Research Group, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand. Tel.: +64 3 364 1186; fax: +64 3 364 0457. E-mail addresses: joanna.young{at}cdhb.govt.nz (J.M. Young).
 |
Abstract
|
|---|
Background: Elevated plasma levels of asymmetric dimethylarginine (ADMA),
an endothelial nitric oxide synthase (eNOS) inhibitor, may contribute
to endothelial dysfunction in chronic heart failure (CHF). Since
statins upregulate eNOS and ameliorate endothelial dysfunction
in non-ischaemic CHF, we hypothesized that this may be in part
through modification of ADMA.
Aim: To evaluate the effect of atorvastatin on the relationship between ADMA and endothelial function in non-ischaemic CHF.
Methods: Twenty-four patients with CHF (ejection fraction <40%, New York Heart Association Functional Classes II and III) were randomised to atorvastatin treatment (40 mg) or placebo once daily for 6 weeks in a double-blinded, placebo-controlled crossover study. Plasma ADMA and L-arginine levels were measured by HPLC. Endothelial function was assessed by flow-mediated dilatation and invasive forearm plethysmography.
Results: Post-statin therapy, endothelial function was improved (p<0.05) independent of LDL-cholesterol reductions, but no changes were observed in ADMA levels or the L-arginine to ADMA ratio. There was a trend for ADMA to inversely correlate with endothelial function at baseline.
Conclusions: Short-term atorvastatin treatment in non-ischaemic CHF improves endothelial function but has no effect on ADMA or the L-arginine to ADMA ratio. Our finding suggests that the observed statin-induced improvements in endothelial function are likely mediated via alternative pathways.
Key Words: Asymmetric dimethylarginine • Left ventricular dysfunction • Chronic heart failure • Statin treatment • Endothelial function
Received September 25, 2007; Revised March 13, 2008; Accepted March 26, 2008
|
1. Background
|
|---|
Amongst the multiple factors implicated in chronic heart failure
(CHF), endothelial dysfunction has emerged as an important feature,
contributing to reduced cardiac output and increased peripheral
vascular resistance
[1]. Endothelial dysfunction is characterised
by dysregulation of the
L-arginine-nitric-oxide pathway
[2].
Plasma levels of asymmetric dimethylarginine (ADMA), a potent
endothelial nitric oxide synthase inhibitor (eNOS), are elevated
in CHF, having been positively associated with disease severity
[3] and increased cardiovascular risk
[4]. ADMA may represent
a novel marker of impaired endothelial function in CHF, thereby
contributing to cardiovascular risk
[5]. Furthermore, the
L-arginine
to ADMA ratio has also been proposed as a potential marker of
endothelial function
[6], with reductions seen in a number of
cardiovascular disease states, including hypertrophic cardiomyopathy
[7]. Statins have been reported to upregulate the expression
and function of eNOS
[8-10], and ameliorate endothelium-dependent
function in non-ischaemic CHF, through lipid-independent pathways
[11]. Whether statin-induced improvements in endothelial function
are mediated through reductions in ADMA in patients with non-ischaemic
CHF is unknown.
|
2. Aims
|
|---|
The present study was designed to investigate the effect of
short-term atorvastatin treatment on plasma ADMA levels and
endothelial dysfunction in patients with stable, non-ischaemic,
left ventricular dysfunction. We hypothesised that statin therapy
would lower ADMA concentrations, and facilitate restoration
of endothelial function in CHF.
|
3. Methods
|
|---|
Twenty-four patients with symptomatic heart failure were randomised
to receive atorvastatin (40 mg) or matching placebo once daily
for 6 weeks in a balanced sequence double-blinded, placebo-controlled
crossover study, with a 2-week washout period between treatments.
A computer generated randomisation list was prepared in advance
and made available to the study pharmacist. Patients were recruited
from Cardiology Outpatient Clinics at the Christchurch Hospital.
Twenty-three patients, aged 60.7±10.4 years, completed
the study and one patient withdrew prior to the first treatment
visit, due to worsening heart failure. Patients had a reduced
left ventricular ejection fraction (30.1±7.7%) and New
York Heart Association Functional Classes II (
n=14) or III (
n=9).
No patient had atrial fibrillation, a prior acute coronary event
or revascularisation, stenotic cardiac valve disease, impairment
of liver, renal (glomerular filtration rate <100 mL/min)
or pulmonary function or was on lipid-modifying medications.
However, four patients had some features of atherosclerotic
disease on angiogram, but with no symptoms of myocardial ischaemia.
Patients were receiving furosemide (
n=18), ACE inhibitor (
n=18)
or angiotensin II receptor antagonist (
n=4) with or without
digoxin (
n=2), a beta-adrenergic blocker (
n=13), spironolactone
(
n=4) and aspirin (
n=14). Patients maintained their standard
anti-failure therapies for the duration of the study period.
Plasma ADMA and
L-arginine were measured by HPLC with fluorescence
detection
[12]. Flow-mediated dilatation [FMD] and glyceryl
trinitrate-induced, endothelium-independent dilatation of the
brachial artery was measured using high-resolution ultrasound
[13]. Endothelium-dependent and independent resistance vessel
function was assessed by forearm venous occlusion plethysmography
during sequential, intra-arterial infusion of acetylcholine,
sodium nitroprusside and
N-monomethyl-
L-arginine (
L-NMMA) alone
or in combination
[14]. Plasma total cholesterol, triglycerides,
and HDL-cholesterol were determined using conventional enzymatic
methods. LDL-cholesterol was calculated from the Friedewald
equation. Measurements were performed at randomisation, and
at the end of both treatment periods. Mean parameters were compared
between placebo and statin therapy using paired-
t-tests. Based
on reported effects of statin treatment on ADMA concentrations
[15], we calculated that 23 patients in a crossover design would
provide sufficient power, at
p<0.05, to detect a clinically
significant effect of statin therapy on reductions in ADMA levels.
Ethical approval was obtained from the Christchurch Ethics Committee.
|
4. Results
|
|---|
Baseline lipid profiles were total cholesterol 5.25±0.20
mmol/L (mean±SEM); LDL-cholesterol 3.32±0.16 mmol/L;
triglycerides 1.60±0.13 mmol/L and HDL-cholesterol 1.22±0.08
mmol/L. Six weeks of atorvastatin therapy resulted in the expected
reductions in total cholesterol (37%), LDL-cholesterol (50%),
and triglycerides (26%) in comparison to placebo (
p<0.001
for all). HDL-cholesterol levels remained unchanged. Statin
treatment improved endothelium-dependent FMD compared to placebo
(1.3% (SEM 0.6)
p<0.05). Moreover, acetylcholine (ACh)-induced
endothelium-dependent vasodilatation of the forearm resistance
vessels (mean AUC±SEM) was greater following atorvastatin
than after placebo (3.72±0.65 vs 2.67±0.48 for
ACh at 15 µg/min (
p=0.015) and 4.59±0.63 vs 3.68±0.53
for ACh at 30 µg/min;
p=0.07). Improved resistance vessel
function was eliminated during co-infusion with
L-NMMA (
p=0.78
for ACh at 15 µg/min and
p=0.69 for ACh at 30 µg/min).
Basal forearm blood flow and endothelial-independent vasodilatation
of the conduit and resistance vessels did not differ between
regimes. There was no change in concentrations of ADMA (
Fig. 1),
or the
L-arginine to ADMA ratio with statin administration compared
to placebo (
p>0.24). However, at baseline there was a trend
for ADMA to correlate with FMD and resistance vessel function
at increasing ACh dosages (
Table 1). Conversely, the
L-arginine
to ADMA ratio was not associated with endothelial-dependent
function (
Table 1) and neither ADMA nor the
L-arginine/ADMA
ratio were correlated with basal forearm blood flow (
Table 1),
LDL-cholesterol (for ADMA
r=–0.14,
p=0.52 and for
L-arginine
to ADMA ratio
r=0.13,
p=0.56) or endothelium-independent vasodilatation.
Statin-induced LDL-cholesterol reductions were independent of
improvements in FMD (
r=–0.27,
p=0.26) and resistance vessel
function (
r=–0.94 (
p=0.71) for ACh at 15 µg/min
and
r=–0.42 (
p=0.08) for ACh at 30 µg/min). Furthermore,
endothelial-dependent vascular function was not associated with
either ADMA or the
L-arginine to ADMA ratio in response to 6
weeks of statin therapy.
View this table:
[in this window]
[in a new window]
|
Table 1 Correlation coefficients for ADMA and the L-Arginine/ADMA ratio versus resistance and conduit function at baseline
|
|
|
5. Conclusions
|
|---|
We demonstrated that short-term treatment with atorvastatin
has no influence on plasma ADMA levels or the
L-arginine to
ADMA ratio in patients with non-ischaemic left ventricular dysfunction,
despite marked improvement in lipid profiles and endothelium-dependent
vasodilatory responses of both the micro and macrovascular circulation.
Statin-induced amelioration of endothelial dysfunction was mainly
independent of LDL-cholesterol reductions, a finding consistent
with comparable studies
[11,
16]. There is evidence that increased
free radical generation, as observed in CHF
[17], may impair
dimethylarginine dimethylaminohydrolase activity and lead to
subsequent ADMA accumulation
[18]. Elevated ADMA levels have
been associated with adverse cardiovascular outcomes in patients
with CHF
[4], but it is unclear whether ADMA may directly impair
endothelial function and thus contribute to increased cardiovascular
risk in CHF. Since the non-lipid mediated benefits of statins
include upregulation of eNOS
[8-10] and alleviation of oxidative
stress
[19], we speculated that atorvastatin would lower ADMA
concentrations and may thereby facilitate restoration of endothelial
function. However, no reductions in ADMA or improvements in
the
L-arginine to ADMA ratio were observed. In previous studies,
statin therapy has been variably linked to modifications in
ADMA levels in hypercholesterolaemic patients
[20,
21] with only
one study demonstrating improved FMD in association with reduced
ADMA levels
[15]. Furthermore, supporting the notion that ADMA
may represent a novel marker of endothelial dysfunction
[4],
we observed a trend for a negative association between ADMA
levels and endothelium-dependent vasodilatation in patients
with CHF. Conversely, there was no trend for a positive association
between the
L-arginine to ADMA ratio and endothelial vasodilator
responses, suggesting the
L-arginine to ADMA ratio may not represent
a marker of endothelial function in non-ischaemic CHF. In conclusion,
if elevated ADMA levels contribute to endothelial dysfunction
in non-ischaemic CHF; our findings could indicate that statin-induced
improvements in endothelium-dependent function are mediated
via alternative pathways to ADMA in these patients.
|
Notes
|
|---|
1 Current address: Diabetes Team Offices, East Wing, Wansbeck
Hospital, Woodhorn Lane, Ashington, Northumberland, NE63 9JJ.
|
References
|
|---|
- Bauersachs J., Schafer A. Endothelial dysfunction in heart failure: mechanisms and therapeutic approaches. Curr Vasc Pharmacol (2004) 2:115–124.[CrossRef][Medline]
- Katz S.D., Schwarz M., Yuen J., LeJemtel T.H. Impaired acetylcholine-mediated vasodilation in patients with congestive heart failure. Role of endothelium-derived vasodilating and vasoconstricting factors. Circulation (1993) 88:55–61.[Abstract/Free Full Text]
- Usui M., Matsuoka H., Miyazaki H., Ueda S., Okuda S., Imaizumi T. Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. Life Sci (1998) 62:2425–2430.[CrossRef][Web of Science][Medline]
- Duckelmann C., Mittermayer F., Haider D.G., Altenberger J., Eichinger J., Wolzt M. Asymmetric dimethylarginine enhances cardiovascular risk prediction in patients with chronic heart failure. Arterioscler Thromb Vasc Biol (2007) 27:2037–2042.[Abstract/Free Full Text]
- Boger R.H. Asymmetric dimethylarginine (ADMA): a novel risk marker in cardiovascular medicine and beyond. Annal Med (2006) 38:126–136.[CrossRef]
- Bode-Boger S.M., Scalera F., Ignarro L.J. The L-arginine paradox: importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacol Ther (2007) 114:295–306.[CrossRef][Web of Science][Medline]
- Dimitrow P.P., Undas A., Bober M., Tracz W., Dubiel J.S. Plasma biomarkers of endothelial dysfunction in patients with hypertrophic cardiomyopathy. Pharmacol Rep (2007) 59:715–720.[Web of Science][Medline]
- Laufs U., La Fata V., Plutzky J., Liao J.K. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation (1998) 97:1129–1135.[Abstract/Free Full Text]
- Kureishi Y., Luo Z., Shiojima I., et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med (2000) 6:1004–1010.[CrossRef][Web of Science][Medline]
- Laufs U., Liao J.K. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem (1998) 273:24266–24271.[Abstract/Free Full Text]
- Node K., Fujita M., Kitakaze M., Hori M., Liao J.K. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation (2003) 108:839–843.[Abstract/Free Full Text]
- Teerlink T., Nijveldt R.J., de Jong S., van Leeuwen P.A.M. Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. Anal Biochem (2002) 303:131–137.[CrossRef][Web of Science][Medline]
- Celermajer D.S., Sorensen K.E., Gooch V.M., et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet (1992) 340:1111–1115.[CrossRef][Web of Science][Medline]
- Watts G.F., O'Brien S.F., Silvester W., Millar J.A. Impaired endothelium-dependent and independent dilatation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes: role of dyslipidaemia. Clin Sci (Lond) (1996) 91:567–573.[Medline]
- Lu T.M., Ding Y.A., Leu H.B., Yin W.H., Sheu W.H.H., Chu K.M. Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Am J Cardiol (2004) 94:157–161.[CrossRef][Web of Science][Medline]
- Tousoulis D., Antoniades C., Vassiliadou C., et al. Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure. Eur J Heart Fail (2005) 7:1126–1132.[Abstract/Free Full Text]
- Keith M., Geranmayegan A., Sole M.J., et al. Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol (1998) 31:1352–1356.[Abstract/Free Full Text]
- Ito A., Tsao P.S., Adimoolam S., Kimoto M., Ogawa T., Cooke J.P. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation (1999) 99:3092–3095.[Abstract/Free Full Text]
- Chen M.S., Xu F.P., Wang Y.Z., et al. Statins initiated after hypertrophy inhibit oxidative stress and prevent heart failure in rats with aortic stenosis. J Mol Cell Cardiol (2004) 37:889–896.[CrossRef][Web of Science][Medline]
- Paiva H., Laakso J., Laine H., Laaksonen R., Knuuti J., Raitakari O.T. Plasma asymmetric dimethylarginine and hyperemic myocardial blood flow in young subjects with borderline hypertension or familial hypercholesterolemia. J Am Coll Cardiol (2002) 40:1241–1247.[Abstract/Free Full Text]
- Valkonen V.P., Laakso J., Paiva H., et al. Asymmetrical dimethylarginine (ADMA) and risk of acute coronary events. Does statin treatment influence plasma ADMA levels? Atheroscler Suppl (2003) 4:19–22.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
Top
Abstract
1. Background