第一節 結果討論
Our study reports that ongoing chronic vascular inflammation, endothelial dysfunction and arterial stiffness abidingly exist in the late KD children with a history of CAA, since the results revealed reduced FMD and increased hs-CRP, ASI and baPWV in these patients. More importantly, we also demonstrate that statin therapy (simvastatin) significantly improves lipoprotein abnormalities, chronic vascular inflammation, endothelial dysfunction and arterial stiffness in KD children with CAA after short-term (3 months) statin treatment, without adverse effects on liver or muscle tissue. To the best of our knowledge, this is the first clinical trial that assessed the effects of statin therapy on lipoprotein, vascular inflammation, endothelial dysfunction and arterial stiffness in the late KD children.
Lipid abnormalities in the acute phase of KD, with decreased TC and HDL-C, are reminiscent of those in acute inflammation, although such changes are transient as reported by several studies [1]. Newburger et al. have reported that HDL-C level remain low as long as three years after the initial illness [17]. Cheung et al. also reported that lower HDL-C and higher LDL-L occurred in children after KD, performed even at a mean of 7.1 years after the initial illness [1]. They also further clarify that low HDL-C level is confined to patients with a history of CAA [1]. In our study, we did not find any significant differences in these lipid profiles between KD patients and normal control group, performed at a mean of 10.77 years after the initial illness. We speculate that the control population is not big enough to reveal the difference. In addition, we also review several studies about the lipid profile changes late after the onset of KD and find that not all of these studies demonstrated the conditions of lower HDL-C and higher LDL-C, like Newburger and Cheung et al.
Maybe, we speculate that all of these current studies, including our study, are cross-sectional studies and do not really represent all the long-term lipid profile changes as their studies.
Hs-CRP was deemed as a powerful marker for chronic vascular wall inflammation and endothelial dysfunction in patients late after the onset of KD [18]. It is well known that inflammatory processes play an important role in the pathogenesis of atherosclerosis. In a meta-analysis of seven prospective studies, elevated hs-CRP was shown to predict future risk of ischaemic stroke, peripheral arterial disease and coronary heart disease [19]. In our study, agreeing with other late KD studies, the hs-CRP value in KD children with CAA was significantly higher than those in normal control. This observation means that chronic low-grade inflammation could persist late after the onset of KD, particularly in those with a history of CAA and would be related to endothelial dysfunction, not only in the vascular wall of coronary arteries but also in the vascular wall of systemic arteries.
Endothelial dysfunction and increased IMT have both been validated as predictors for further cardiovascular disease. Endothelium-dependent FMD of the brachial artery has been used to assess the endothelial function, mainly due to its nitric oxide (NO) releasing function by the endothelium, which is also well correlated with coronary endothelial function. Several other reports have shown that there were systemic endothelial dysfunction late after the onset of KD, as reflected in the FMD
dysfunction of brachial artery, particularly in those children with a history of CAA [5,9,24]. In our study, we also showed significantly decreased FMD of brachial artery as compared to normal control. Increase of IMT is also a strong risk factor for early atherosclerosis and premature onset of cardiovascular disease. KD children with CAA have been proved to manifest an increase of IMT [12, 25]. This phenomenon was not
so that our data can not reveal the significant difference in IMT when compared with normal control.
Impaired endothelial function has been demonstrated in KD patients with CAA in previous and our studies [9,20]. Inflammatory responses observed in our patients late after KD are also consistent with previously documented endothelial dysfunction in such patients. This residual endothelial dysfunction in the chronic stage of KD is supposed to be induced by the strong systemic inflammation during the acute stage of KD [26]. Because endothelium-derived nitric oxide (NO) inhibits the expression of adhesion molecules, decreased NO release may upregulate the expression of these molecules. In addition, because NO has antioxidant properties, the decreased NO production may unmask local inflammatory responses [21]. Moreover, CRP directly reduces NO production from endothelial cells and increases its expression of adhesion molecules [22]. The exposure of endothelial cells to proinflammatory cytokines impairs the endothelium-dependent vasodilating function [23]. Therefore, elevated CRP levels may be associated with chronic endothelial dysfunction in KD patients.
Echocardiography or coronary angiography accurately evaluates coronary aneurysms and stenotic lesions, but they can not assess the early progression of systemic atherosclerosis. PWV and ABI have been reported as useful and simple methods to evaluate the degree of atherosclerosis in adults, and are considered as powerful markers and predictors for cardiovascular disease [27].PWV measurement as a surrogate for arterial stiffness was first reported in 1922, but only recently were automated devices available. It is non-invasive and has been validated repeatedly.
PWV increases as arteries become more damaged and stiffer. In our study, we showed that the KD patients with a history of CAA had significantly higher ASI and faster baPWV than normal control. This might be suggesting that the systemic arteritis from the acute stage of KD has been resulted in a structural change in the arterial wall,
which manifests as an age-related increase of arterial stiffness in the long term follow up [27]. Our study revealed that the KD children with a history of CAA had systemic vascular endothelial dysfunction and arterial stiffness, and also suggested that the KD complicated with CAA is likely to prompt early development of atherosclerosis.
Although there was a significant difference in another markers and index, ABI showed no significant difference between the KD and the normal control. ABI reflects arteriosclerotic angiopathy, and ABI ≦0.9 was regarded as an independent risk factor for cardiovascular disease. We speculate that it may be due to our KD children are still in the early reversible stage of endothelial dysfunction and atherosclerosis, not yet severe to reveal abnormal arteriosclerotic angiopathy. Besides, no patient in our study had symptoms of clinical sclerotic arteriopathy [27].
Statins, hydroxymethylglutaryl coenzyme A reductase inhibitors, have been proven to not only reduce LDL-C level, but also improve surrogate markers of atherosclerosis and endothelial dysfunction [28]. Statins also have several important pleiotropic properties, such as improvement of endothelial dysfunction, inhibition of inflammatory responses, stabilization of atherosclerotic plaques, and modulation of procoagulant activity and platelet function [29]. In fact, clinical studies have suggested that the beneficial effects of statin treatment begin earlier than the cholesterol-lowering effect [29].
More recently, several prospective studies have shown that statin therapy reduces hs-CRP, and that the lower the hs-CRP the lower the event rate and the slower the progression of atherosclerosis, independent of LDL-C level [7]. A possible mechanism for this action of statins is that inhibition of cholesterol synthesis interferes with the formation of lipid rafts on the surface of lymphocytes. This in turn interferes with lymphocyte function and thereby reduces inflammation [30]. Like
hs-CRP in the late KD children with CAA after a short-term statin treatment.
However, a long-term and large sample prospective studies using hs-CRP as a guide of therapy are needed.
Arambepola et al. conducted a systematic review and meta-analyses to assess the evidence for efficacy and safety of statin therapy in children and adolescents with heterozygous familial hypercholesterolaemia (FH) [31]. They showed that statins lowered LDL-C 32.5% (95% CI 24.3, 40.7), increased HDL-C 3.4% (0.8, 6.0), insignificantly lowered TG 3.0% (-11.6, 17.6), attenuated progression of carotid IMT, and improved endothelial function (increased % FMD of brachial artery). None reported a significant difference in growth, sexual maturation and any significant increases of ALT, AST and CK values [31]. In our study for KD patients, the improvement of TC, LDL-C, TG and HDL-C levels are also compatible to their studies of statin therapy in children of FH. In agree with Arambepola’s study, our study also revealed attenuation of IMT progression in the carotid artery, and improvement of endothelial dysfunction and arterial stiffness after only 3 months of statin treatment in the late KD children complicated with CAA.
Statin therapy significantly improved endothelial dysfunction (increased % FMD of brachial artery) in children with FH after 28 weeks of therapy [28]. Remarkable lipid lowering by statin was also accompanied by carotid IMT regression in FH children [32]. These findings suggested that initiation of statin therapy in children may inhibit the progression of atherosclerosis, even leading to its regression [10,32]. Recent numerous studies have shown that the statins' cholesterol-independent vascular effects may be directly improving the endothelial function by increasing its NO production (by upregulating endothelial cell NO synthase through stabilization of messenger ribonucleic acid levels), promoting re-endothelialization after arterial injury and inhibiting inflammatory responses within the vessel wall [29]. The study of statin
therapy in FH has proved that the peripheral endothelial dysfunction can be completely reversedafter only short-term of statin therapy [33]. However, in patients with chronic coronary artery disease, the statin therapy can only attenuate the acetylcholine-induced “paradoxical” vasoconstriction, but it has no effect on the endothelium-dependent vasodilation [34]. These findings emphasize that in order to achieve normalization of endothelial function in “atherogenic” vascular beds, such as the coronary arteries, the statin therapy well need to be initiated at an early stage, before the onset of severe macrovascular structural abnormalities [28]. We believe that early statin therapy is helpful in restoring endothelial dysfunction and arterial stiffness in their reversible stage and prevent the future cardiovascular events [5].
However, what is the long term end point of statin therapy to protect the pediatric patients of KD from later cardiovascular events remains unsettled. Does delaying initiation of statin therapy until adulthood benefit the KD patients as much as the early therapy since childhood? Nevertheless, the demonstrations of early developing of atherosclerosis in many follow up studies of KD and the disability of late statin therapy to revert endothelial dysfunction in atherogenic vessels have made the early initiation of statin therapy an important issue.
In the present cohort study, no toxicity or serious adverse effects were found throughout the study. However, the follow up period of the present study is too short to draw conclusions on the safety of long-term use of simvastatin in KD children. The series of Wiegman et al have reported that two years of pravastatin therapy in children of FH did not cause any adverse effects on their growth, sexual maturation, hormone levels, or liver or muscles tissue [32].
第二節 研究限制
This study has several limitations, including a small sample size, short duration and lack of a group of KD patients without using statin for comparison. Lifestyle changes were also not actively monitored or controlled. Besides, our study is a cross-sectional and short-term clinical trial, and the cardiovascular improvement by statin therapy in this study is not able to predict a long term benefit in preventing future cardiovascular events.