Atherosclerosis 154 2001 171 – 177
The effect of amlodipine on endothelial function in young adults with a strong family history of premature coronary artery disease:
a randomised double blind study
Peter Clarkson, Michael J. Mullen, Ann E. Donald, Amanda J. Powe, Hyeyoung Thomson, Sara A. Thorne, Teresa Bull, John E. Deanfield
Cardiothoracic Unit, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC
1
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3
JH, UK Received 9 April 1999; received in revised form 17 February 2000; accepted 25 February 2000
Abstract
Endothelial dysfunction, an early event in atherogenesis, has been demonstrated in young asymptomatic subjects with a strong family history of premature coronary artery disease CAD. In these subjects, preventive measures involving risk factor
modification are not appropriate, and strategies employing novel antiatherogenic agents, such as the dihydropyridine calcium channel blocker, amlodipine, may be useful. Ninety-one subjects mean age, 28.6 years; range, 18 – 40 with a strong family history
of premature CAD and no other identified vascular risk factors were randomised to either 5 mg amlodipine 49 subjects or placebo 42 subjects. Brachial artery flow mediated dilatation FMD endothelium-dependent response and response to
glyceryltrinitrate GTN direct smooth muscle dilator were assessed non-invasively at baseline, and after 12 and 24 weeks using high-resolution vascular ultrasound. In those treated with amlodipine, mean FMD increased from 2.32 9 2.23 at baseline to
3.52 9 3.1 at 24 weeks P B 0.005. However, FMD also increased in the placebo group from 1.64 9 2.12 to 3.37 9 2.68 P B 0.002, and the difference between the FMD response in the amlodipine and placebo groups was not significant. Dilatation
to GTN did not change in either group. Therefore, impaired endothelial function improved in family history subjects taking both amlodipine and placebo, but there is no difference between the groups. © 2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords
:
Endothelium; Amlodipine; Ultrasound; Family history www.elsevier.comlocateatherosclerosis
1. Introduction
A history of premature coronary artery disease CAD in a first-degree relative is an independent risk
factor for coronary heart disease [1 – 5] and may convey a 2.5- to 7-fold increase in risk of death from coronary
disease [6]. Although this inherited vascular risk may be mediated by genetically influenced cardiovascular risk
factors, including diabetes and hyperlipidaemia [7 – 10], it is also likely that a variety of genes interact to alter
the arterial wall andor its susceptibility to damage from risk factors [11].
Damage to the vascular endothelium is an initiating event in experimental studies of atherogenesis [12]. This
is thought to involve reduced activity of nitric oxide NO [13,14], a key ‘anti-atherogenic’ molecule that not
only modifies vascular tone, but also plays a key role in regulating vascular permeability, platelet adhesionag-
gregation, leukocytevessel wall interaction and smooth muscle proliferation [15], all recognised events in early
atherosclerotic vascular disease.
Endothelial dysfunction has been demonstrated in young, asymptomatic, subjects who have established
cardiovascular risk factors, such as smoking, hyperc- holesterolaemia and diabetes, and patients with estab-
lished atherosclerosis [16 – 19]. In these preclinical subjects, experimental studies have shown that targeted
risk factor modification, such as aggressive cholesterol reduction, has led to improved endothelial function
Abbre6iations
:
CAD, coronary artery disease; CCB, calcium chan- nel blocker; NO, nitric oxide; FMD, flow mediated dilatation; GTN,
glyceryl trinitrate; LDL, low density lipoprotein; HDL, high density lipoprotein; ECG, electrocardiogram.
Corresponding author. Tel.: + 44-0207-813-8223; fax: + 44- 0207-813-8352.
E-mail address
:
peterclarkson1compuserve.com P. Clarkson. 0021-915001 - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved.
PII: S0021-91500000455-X
[20]. Clinical studies involving similar interventions have demonstrated further long-term benefits in re-
duced cardiovascular morbidity and mortality [21]. Similarly, impaired endothelium-dependent dilatation,
an early marker of endothelial dysfunction, has re- cently been demonstrated in the conduit arteries of
young adults whose only identifiable vascular risk fac- tor is a strong family history of CAD [22]. These
individuals have no obvious modifiable risk factors and conventional preventative strategies may not be
appropriate.
In established atherosclerotic disease, the potential role of calcium channel blockers CCB has been ex-
amined with angiographic regressionprogression [23 – 25], and now morbidity and mortality studies [26].
Experimental evidence also suggests that CCB may play a role in disease development, but this has not
been studied clinically [27]. The mechanism by which CCB exert this anti-atherogenic effect is uncertain but
might involve the suppression of smooth muscle cell SMC proliferation and connective tissue migration in
the vascular wall [28]. Amlodipine, a highly lipophillic dihydropyridine CCB, has been shown to have addi-
tional properties, inhibiting the oxygen free radicals involved in lipid peroxidation [29], stabilising cell
membrane lipid bilayers [30] and preventing vascular endothelial damage in cholesterol fed primates [31]. As
this agent has been widely used clinically and is well tolerated, it was felt it might represent a novel thera-
peutic approach applicable to family history subjects.
Therefore, the effects of the CCB amlodipine on conduit artery endothelial function was examined in a
cohort of young adults whose only identifiable cardio- vascular risk factor was a family history of premature
CAD, to determine whether improvements of poten- tial clinical significance could be achieved at this early
stage in the natural history of atherosclerotic disease.
2. Methods
