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Cardiovascular complications—coronary artery structure and function
Progress in Pediatric Cardiology 19 (2004) 147 – 152 www.elsevier.com/locate/ppedcard
Cardiovascular complications—coronary artery structure and function Brian W. McCrindle* Division of Cardiology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8 Received 5 June 2004; accepted 25 August 2004 Available online 7 October 2004
Abstract During the convalescent phase of Kawasaki disease, structural and functional abnormalities of the coronary and systemic arteries are variably present, and may be independent of the degree of coronary artery involvement during the acute phase of illness. Endothelial dysfunction is the earliest precursor in the development of the atherosclerotic disease process, and its presence and persistence in Kawasaki disease patients remain of concern. In addition, the vascular wall structure is altered in areas of persistent but also possibly bhealedQ involvement. There is concern that these functional and structural abnormalities may lead to accelerated atherosclerosis and earlier manifest cardiovascular disease. These abnormalities raise the possibility that patients who have had Kawasaki disease may merit screening and management of cardiovascular risk factors and ongoing follow-up. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Kawasaki disease; Coronary artery; Endothelium; Myocardial flow reserve
Since the original description of Kawasaki disease, the subsequent 30 years of observation and investigation have led to an increased understanding of the acute and long-term coronary artery complications. Initial descriptions of coronary artery pathology were limited to assessments of the coronary artery lumen as assessed by two-dimensional echocardiography and coronary artery angiography. These studies have given detailed accounts of changes within the lumen of the coronary artery branches in terms of dilatation and aneurysm formation and their regression and resolution. Current definitions of coronary artery involvement rest on the measurement of proximal coronary artery luminal diameters and their degree of deviation from normal based on patient age or body size. The assessment of the coronary artery lumen, however, is a limited indicator of the presence of both functional and structural pathology within the vascular wall. The presence of a normal luminal dimension does not preclude the presence of coronary artery involvement, either in the acute or the convalescent phases. There have been rapid developments in both functional assessment * Tel.: +1 416 813 7610; fax: +1 416 813 7547. E-mail address: [email protected]. 1058-9813/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ppedcard.2004.08.008
and structural imaging of the coronary artery vasculature which have shed new light on the spectrum of coronary artery pathology. In addition, findings from these developments have raised concerns regarding ultra long-term outcome for patients with varying degrees or severity of coronary artery involvement. Of greatest concern is the ongoing question of whether patients who have had either no or minimal and resolved coronary artery involvement are at risk for accelerated atherosclerosis and premature cardiovascular events in their adult years.
1. Coronary artery pathology Given the low mortality associated with Kawasaki disease, the pathology of coronary artery disease and its regression has been described only in limited autopsy studies usually including patients who died with severe coronary artery involvement. Amano et al. [1] described pathological material from 37 autopsied patients. They noted that initial damage to the endothelial cells lead to degeneration and increased vascular permeability and platelet aggregation. This was followed by edema and degeneration of media with
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destruction of smooth muscle cells. Incidentally, they also noted vascular pathology in the venous system as well. Nakatani et al. [2] have recently reported the presence of circulating endothelial cells and endothelial progenitor cells in acute and subacute Kawasaki disease patients, which were more marked in those with coronary artery lesions. Iizuka et al. [3] have noted that abnormally high quantities of nitric oxide were excreted in acute Kawasaki disease patients, which may explain the high prevalence of coronary artery dilation. Fujiwara et al. [4] studied 69 autopsied infants, and noted that a panvasculitis was evident in the acute stages in aneurysmal segments. Healed aneurysmal segments were marked by intimal thickening, although thrombi were also noted with some recanalization. In nonaneurysmal segments, acute inflammation was more localized to the intima and perivascular area of the coronary arteries, followed by less marked intimal thickening. The nature of the acute and convalescent cellular infiltrate has been a focus of study. Koygoku [5] felt that initial seroexudative inflammation was followed by a transient granulocyte-leading stage. This lead to a final lymphocytic interstitial infiltration. Rowley et al. [6] noted early vascular infiltration with IgA plasma cells, and felt that this was evidence for a conventional antigen-driven immune response. Sasaguri and Kato [7] studied five aneurysms from four patients, and noted marked intimal thickening in all. They suggested that thrombosis in the aneurysms had an impact on their fate. Two aneurysms in patients treated with aspirin showed no evidence of thrombosis and a well-regenerated endothelium with marked intimal thickening rich in smooth muscle cells. In contrast, aneurysms in two patients not treated early with aspirin showed massive thrombus formation with calcification as well as intimal thickening. Takahashi et al. [8] studied six autopsy cases. Intimal thickening was noted in nonaneurysmal segments, while thrombotic occlusion occurred in four of six persistent aneurysms, with one patient showing advanced atherosclerotic changes. Those with recanalized aneurysms showed new intimal thickening which progressed to occlusion in some. From this evidence, a picture of the pathology of the coronary arteries can be derived. In the acute phase of Kawasaki disease, there is evidence of endothelial dysfunction and damage, which may be manifest by coronary artery dilation. The pathologic process may also progress to include inflammatory-mediated changes within all layers of the arterial structure. These can lead to weakening and destruction of supportive elements of the vascular wall which, under the presence of hydrostatic forces, can result in aneurysm formation and rarely rupture. Very large aneurysms can represent areas of flow stasis [9] which, together with the presence of endothelial dysfunction and platelet activation, promote the development of thrombosis. These thrombi can be occlusive and may lead to sudden myocardial infarction or they can be laminar along the vessel wall and lead to a reduction in the luminal size. During the convalescent phase, aneurysms tend to heal through progressive intimal prolifer-
ation and neoangiogenesis, which may be mediated by the persistence and extensive expression of vascular growth factors [10]. This may eventually reduce the luminal dimension to a normal size. Nonetheless, these healed aneurysms demonstrate varying thick and stiff vascular walls with persistence of abnormal endothelial function. It is yet unknown but concerning that these alterations in structure and function may lead to an acceleration of the atherosclerotic disease process.
2. Structural imaging New methods have been used to assess the structure of the vascular wall of the coronary arteries. Intravascular ultrasound has been used at the time of cardiac catheterization to assess arterial wall morphology and luminal dimensions in patients who have had Kawasaki disease. Sugimura et al. [11] reported the use of intravascular ultrasound to assess 20 patients, including 10 patients with persistent or regressed aneurysms, 2 patients who had Kawasaki disease but had never had coronary artery involvement, and in 8 normal control subjects. They noted that at sites of regressed aneurysms there was a markedly thickened but smooth intimal surface. Iemura et al. [12] assessed 27 patients more than 10 years after their initial episode of acute Kawasaki disease, including 9 with regressed large aneurysms, 9 with regressed small aneurysms, 4 with both regressed small and large aneurysms, and 5 with no aneurysms. In addition, six normal patients with congenital heart disease were studied as normal controls. In all 27 patients, the coronary artery angiogram showed normal luminal dimensions. Using intravascular ultrasound, they noted that the thickness of the intima-media complex in those with regressed large aneurysms was a mean of 0.59 mm versus 0.29 mm in those with regressed small aneurysms. No abnormalities were noted in segments that had not been previously involved or in the normal control patients. Suzuki et al. [13] used intravascular ultrasound to assess 23 patients at a mean of 11.5 years after Kawasaki disease. The intima-media complex was thickest in those coronary artery segments with regressed aneurysms (mean 0.84 mm) versus those with persistent aneurysms (mean 0.54 mm). Mild thickening was noted in angiographically normal segments (mean 0.22 mm).
3. Functional abnormalities of the coronary arteries The endothelium plays a central role in the regulation of numerous functions of a healthy artery [14]. A healthy endothelium is represented by an intact regulatory smooth antithrombotic, profibrinolytic and anti-inflammatory surface. Many of these functions are mediated through the central role of nitric oxide. These nitric oxide-mediated roles can be impaired through damaging factors that impart an
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oxidative stress. These damaging factors may set in motion the cascade of changes that lead to atherosclerosis, which is a nonspecific vascular healing response. The endothelium can be assessed by its response to various vascular stimuli. Arterial dilation in response to acetylcholine or reactive hyperemia is felt to be mediated through endogenous nitric oxide pathways functioning in a healthy endothelium. Arterial dilation can also be elicited by measuring the vasodilatory response to exogenous nitric oxide, which is felt to be independent of the endothelium. These responses can be assessed invasively in the coronary artery vasculature or noninvasively in superficial arteries. The assessment in superficial systemic arteries does have some correlation to those responses and the presence of disease in the coronary arteries. Mitani et al. [15] used quantitative coronary artery angiography to assess responses to intraluminal infusions of acetylcholine and nitroglycerin. In response to acetylcholine, Kawasaki disease patients had less vasodilation than normal control subjects, regardless of the magnitude of coronary artery involvement. In response to nitroglycerin, vasodilation was least in those with persistent or regressed aneurysms, with those without involvement intermediate relative to normal control subjects. They also assessed reactivity in the superficial femoral arteries, and noted no difference compared to normal control subjects in responses to either reactive hyperemia or nitroglycerin. Likewise, Yamakawa et al. [16] used quantitative angiography to assess responses to acetylcholine in 25 Kawasaki disease patients and 10 normal control subjects. In response to intracoronary infusion, segments with regressed aneurysms showed vasoconstriction, while segments with persistent aneurysms showed no response. Uninvolved segments in Kawasaki disease patients showed similar amounts of vasodilation compared to normal control subjects. The potential clinical relevance of these functional changes can be assessed using positron admission tomography (PET) to quantify myocardial blood flow and myocardial flow reserve in response to provocative maneuvers. Furuyama et al. [17] used PET scanning to study myocardial blood flow in 12 patients with regressed aneurysms in the region of the left anterior descending and in 12 normal control subjects. They noted that while myocardial blood flow at rest was similar in the two groups, in response to adenosine triphosphate, the Kawasaki disease patients had reduced flow, which translated into a reduction in myocardial flow reserve. They likewise had a reduced ratio myocardial blood flow at rest versus with cold pressor testing versus the normal controls. They concluded that there was impaired myocardial blood flow and that endothelial dysfunction was present in the area of the regressed aneurysms. A further study by Furuyama et al. [18] showed that myocardial flow reserve was most reduced in regions distal to a stenosis (Fig. 1). Regions supplied by arteries with either persistent or regressed coronary aneurysms also had less marked reductions in myocardial flow reserve. Areas
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Fig. 1. Impaired myocardial flow reserve in coronary artery segments with varying degrees of involvement after Kawasaki disease compared to a normal control group. Compared to normals, all myocardial regions in the Kawasaki disease patients had reduced reserve, significantly lower in areas supplied by a stenotic coronary artery segment. Adapted from Furuyama et al. [18].
supplied by segments that had never been involved also showed reductions in myocardial flow reserve in comparison to normal control subjects. Regardless of the level of coronary artery involvement the change in myocardial blood flow with cold pressor stress was reduced in all segments compared to the normal controls. Muzik et al. [19] also quantified myocardial blood flow and flow reserve using PET scanning in Kawasaki disease patients. They studied 10 children with a history of Kawasaki disease and 10 healthy adult controls. The study was unique in that none of the Kawasaki disease patients had had any luminal changes during the acute or convalescent stages. Myocardial blood flow at rest was similar in both patient and control groups. However, in response to hyperemic blood flow induced by adenosine stress, the myocardial blood flow was significantly lower in the Kawasaki disease patients, with lower estimates of myocardial flow reserve and higher total coronary resistance (Fig. 2). A quantitative analysis of perfusion images demonstrated no evidence of regional perfusion abnormalities in either study group. They concluded that these patients had impaired vasodilatory capacity and that damage might reside in the coronary artery microcirculation. Hauser et al. [20] likewise studied myocardial blood flow and flow reserve using PET scanning. They studied 10 patients with Kawasaki disease who all had an initial aneurysm in their coronary arteries with complete resolution during follow-up. They compared them to 10 normal control subjects and noted that myocardial blood flow at rest was similar in the two groups but impaired in response to provocation with adenosine stress with reduced coronary flow reserve. Again, no stress-induced perfusion defects were noted. A relationship between structural and functional changes has been defined. Iemura et al. [12] also assessed coronary artery function as part of their study of intravascular
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Fig. 2. Impaired myocardial blood flow and flow reserve in coronary arteries assessed by positron emission tomography in Kawasaki disease patients with no history of coronary artery involvement. Myocardial blood flow in response to adenosine-induced vasodilation was significantly lower in the patients versus healthy adult controls ( p=0.01) with lower myocardial flow reserve ( p=0.003). Adapted from Muzik et al. [19].
ultrasound. Using intraluminal infusions of nitroglycerine, they assessed arterial vasodilatation as a measure of an endothelium-independent response. They noted that vasodilatation was most reduced in those with segments with regressed large aneurysms, followed by those with regressed small aneurysms with those segments having no structural abnormalities and in the normal controls showing normal amounts of vasodilatation. They also assessed vasodilatation in response to acetylcholine, which is a measure of endothelium-dependent response. They noted that in those segments with regressed large aneurysms there was marked vasoconstriction with a lesser degree of vasoconstriction in those segments with regressed small aneurysms. In those segments assumed to be normal, there was significantly less vasodilatation than that seen in those of the normal control subjects. Similar findings were noted in the intravascular ultrasound study by Suzuki et al. [13]. These studies therefore suggest that in areas of healed aneurysms there is considerable stiffness of the vascular wall with markedly abnormal function of the endothelium. In those segments presumed to have had no coronary artery involvement, while there does not appear to be excessive stiffness, some element of endothelial dysfunction may be present. Nonetheless, these functional changes did not translate into any abnormalities regarding perfusion. The relevance in terms of an increased risk for acceleration of the atherosclerotic disease process is as yet unknown.
on assessments of endothelial dysfunction in both the coronary artery vasculature and the systemic arterial bed. Dhillon et al. [21] used vascular ultrasound to study reactivity in the brachial artery. They studied 20 patients at a median of 11 years after their acute Kawasaki disease episode, and compared them to results in 20 age- and gender-matched controls. They noted no differences in baseline lipid profile values. In response to reactive hyperemia, a measure of endothelium-dependent vasomotion, they noted a mean dilatation of 3.1% in the Kawasaki disease patients versus 9.4% in the control subjects, a difference that was statistically significant. In response to sublingual glyceryl trinitrate, a measure of endotheliumindependent vasomotion, the mean amount of dilatation was 23% in the patients versus 21.7% in the controls. This study suggested that endothelial dysfunction is present, possibly throughout the systemic arterial bed, in patients who have had Kawasaki disease. These results are in contrast to those of Silva et al. [22] who, in a similar case-control study, noted no significant differences in either flow-mediated or nitroglycerine-mediated vasodilatation in the brachial artery of the Kawasaki disease patients. They did assess numerous other cardiovascular risk factors for atherosclerosis and did note some significant differences. Deng et al. [23] assessed 39 patients at a mean of 7.1 years after their Kawasaki disease episode, and compared them to 17 age- and gender-matched control subjects. They noted abnormalities in flow-mediated but not nitroglycerinemediated brachial artery reactivity in the Kawasaki disease patients. They then gave half of the Kawasaki disease patients an intravenous dose of vitamin C and noted that the flow-mediated dilatation improved to near normal (Fig. 3). This would suggest that the use of antioxidant vitamin, vitamin C, reduced oxidative stress that may be present in patients after Kawasaki disease and improved endothelial function.
4. Are Kawasaki disease patients at increased risk for accelerated or premature atherosclerosis? There has been some debate whether having had Kawasaki disease confers an added risk for premature or accelerated atherosclerosis. Much of this debate has focused
Fig. 3. Improved endothelial function of the brachial artery after infusion of vitamin C in Kawasaki disease patients. Endothelium-dependent vasodilation as provoked by reactive hyperemia was reduced in Kawasaki disease patients but improved significantly with an intravenous administration of vitamin C. Adapted from Deng et al. [23].
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has been increasing in the Kawasaki disease cohort with successively longer follow-up, the overall standardized mortality ratio continues to fall. It is higher for males than for females, and the increase seems to be most marked in those males within the first 2 months of the acute episode or in males with cardiac involvement. The fact that the standardized mortality ratio continues to decrease with progressive follow-up suggests that these patients have not yet manifest any evidence for premature mortality.
5. Summary
Fig. 4. Greater intima-media thickness with greater stiffness of the carotid arteries after Kawasaki disease. Adapted from Noto et al. [25].
Albisetti et al. [24] studied 42 patients in the convalescent phase after acute Kawasaki disease, 22 of whom had never had any luminal abnormalities of their coronary arteries. They compared the results to 26 age- and gendermatched control subjects, and used venous occlusion stress testing to assess fibrinolytic capacity as a measure of endothelial function. At baseline, they noted that the patients had higher fibrinogen, plasminogen, and alpha-2 macroglobulin levels. The Kawasaki disease patients showed a decreased fibrinolytic response to the stress testing with a decrease in tissue plasminogen activator antigen. These abnormalities were not related to the degree of coronary artery luminal changes. Vascular ultrasound can also be used to assess structural changes that may be indicative of early progression of atherosclerosis. These are usually assessed in the carotid arteries by measuring the thickness of the intima-media complex. Noto et al. [25] assessed 20 patients who had had coronary artery lesions after Kawasaki disease and compared them to 20 age- and gender-matched controls (Fig. 4). They found no difference in baseline lipid profile values, blood pressure or body mass index, although the Kawasaki disease patients were noted to have a higher hemoglobin A1c levels. From carotid artery ultrasound, they noted that the Kawasaki disease patients had a slight but statistically significant increase in the thickness of the intima-media complex, and a more marked increase in the stiffness index of the carotid arteries, suggesting the presence of early systemic vascular changes. In light of these structural and functional changes in both the coronary arterial and systemic arterial beds, concerns will linger as to whether these patients will have a future of premature atherosclerotic cardiovascular disease. Unfortunately, follow-up of Kawasaki disease patients has not yet been sufficiently long to determine if this is apparent. Nakamura et al. have been following a cohort of Kawasaki disease patients assembled from 1982 to 1992 in Japan, and comparing their mortality to that of a similar age- and gender-matched cohort [26–30]. While the number of deaths
Structural and functional abnormalities of the coronary and systemic arteries are present in patients in the convalescent phase of Kawasaki disease, and may be independent of the degree of initial coronary artery involvement as noted by assessment of the vascular lumen. Endothelial dysfunction is the earliest precursor in the development of the atherosclerotic disease process, and its presence and persistence in Kawasaki disease patients remain of concern. It is controversial how this should be addressed in the long-term follow-up and management of Kawasaki disease patients with varying degrees of initial and regressed or resolved coronary artery involvement [31]. As a minimum, patients who have had Kawasaki disease should be counseled as to cardiovascular risk factors for atherosclerosis and their reduction. Controversial areas include whether Kawasaki disease patients should be screened for all known cardiovascular risk factors, and whether patients who have had no coronary artery involvement or only transient dilatation that resolved should require long-term cardiology follow-up and evaluation. Clear evidence is needed to address this controversy.
References [1] Amano S, Hazama F, Hamashima Y. Pathology of Kawasaki disease: I. Pathology and morphogenesis of the vascular changes. Jpn Circ J 1979;43:633 – 43. [2] Nakatani K, Takeshita S, Tsujimoto H, Kawamura Y, Tokutomi T, Sekine I. Circulating endothelial cells in Kawasaki disease. Clin Exp Immunol 2003;131:536 – 40. [3] Iizuka T, Oishi K, Sasaki M, Hatanaka Y, Minatogawa Y, Uemura S, et al. Nitric oxide and aneurysm formation in Kawasaki disease. Acta Paediatr 1997;86:470 – 3. [4] Fujiwara H, Fujiwara T, Kao TC, Ohshio G, Hamashima Y. Pathology of Kawasaki disease in the healed stage. Relationships between typical and atypical cases of Kawasaki disease. Acta Pathol Jpn 1986; 36:857 – 67. [5] Kyogoku M. A pathological analysis of Kawasaki disease—with some suggestions of its etio-pathogenesis. Prog Clin Biol Res 1987;250:257 – 73. [6] Rowley AH, Eckerley CA, Jack HM, Shulman ST, Baker SC. IgA plasma cells in vascular tissue of patients with Kawasaki syndrome. J Immunol 1997;159:5946 – 55. [7] Sasaguri Y, Kato H. Regression of aneurysms in Kawasaki disease: a pathological study. J Pediatr 1982;100:225 – 31.
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[8] Takahashi K, Oharaseki T, Naoe S. Pathological study of postcoronary arteritis in adolescents and young adults: with reference to the relationship between sequelae of Kawasaki disease and atherosclerosis. Pediatr Cardiol 2001;22:138 – 42. [9] Kuramochi Y, Ohkubo T, Takechi N, Fukumi D, Uchikoba Y, Ogawa S. Hemodynamic factors of thrombus formation in coronary aneurysms associated with Kawasaki disease. Pediatr Int 2000;42:470 – 5. [10] Suzuki A, Miyagawa-Tomita S, Komatsu K, Nishikawa T, Sakomura T, Horie T, et al. Active remodeling of the coronary arterial lesions in the late phase of Kawasaki disease: immunohistochemical study. Circulation 2000;101:2935 – 41. [11] Sugimura T, Kato H, Inoue O, Fukuda T, Sato N, Ishii M, et al. Intravascular ultrasound of coronary arteries in children. Assessment of the wall morphology and the lumen after Kawasaki disease. Circulation 1994;89:258 – 65. [12] Iemura M, Ishii M, Sugimura T, Akagi T, Kato H. Long term consequences of regressed coronary aneurysms after Kawasaki disease: vascular wall morphology and function. Heart 2000; 83:307 – 11. [13] Suzuki A, Yamagishi M, Kimura K, Sugiyama H, Arakaki Y, Kamiya T, et al. Functional behavior and morphology of the coronary artery wall in patients with Kawasaki disease assessed by intravascular ultrasound. J Am Coll Cardiol 1996;27:291 – 6. [14] Widlansky ME, Gokce N, Keaney JF, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003;42: 1149 – 60. [15] Mitani Y, Okuda Y, Shimpo H, Uchida F, Hamanaka K, Aoki K, et al. Impaired endothelial function in epicardial coronary arteries after Kawasaki disease. Circulation 1997;96:454 – 61. [16] Yamakawa R, Ishii M, Sugimura T, Akagi T, Eto G, Iemura M, et al. Coronary endothelial dysfunction after Kawasaki disease: evaluation by intracoronary injection of acetylcholine. J Am Coll Cardiol 1998; 31:1074 – 80. [17] Furuyama H, Odagawa Y, Katoh C, Iwado Y, Yoshinaga K, Ito Y, et al. Assessment of coronary function in children with a history of Kawasaki disease using (15)O-water positron emission tomography. Circulation 2002;105:2878 – 84. [18] Furuyama H, Odagawa Y, Katoh C, Iwado Y, Ito Y, Noriyasu K, et al. Altered myocardial flow reserve and endothelial function late after Kawasaki disease. J Pediatr 2003;142:149 – 54. [19] Muzik O, Paridon SM, Singh TP, Morrow WR, Dayanikli F, Di Carli MF. Quantification of myocardial blood flow and flow reserve in children with a history of Kawasaki disease and normal coronary arteries using positron emission tomography. J Am Coll Cardiol 1996; 28:757 – 62.
[20] Hauser M, Bengel F, Kuehn A, Nekolla S, Kaemmerer H, Schwaiger M, et al. Myocardial blood flow and coronary flow reserve in children with bnormalQ epicardial coronary arteries after the onset of Kawasaki disease assessed by positron emission tomography. Pediatr Cardiol 2004;25:108 – 12. [21] Dhillon R, Clarkson P, Donald AE, Powe AJ, Nash M, Novelli V, et al. Endothelial dysfunction late after Kawasaki disease. Circulation 1996;94:2103 – 6. [22] Silva AA, Maeno Y, Hashmi A, Smallhorn JF, Silverman ED, McCrindle BW. Cardiovascular risk factors after Kawasaki disease: a case-control study. J Pediatr 2001;138:400 – 5. [23] Deng YB, Li TL, Xiang HJ, Chang Q, Li CL. Impaired endothelial function in the brachial artery after Kawasaki disease and the effects of intravenous administration of vitamin C. Pediatr Infect Dis J 2003;22:34 – 9. [24] Albisetti M, Chan AK, McCrindle BW, Wong D, Vegh P, Adams M, et al. Fibrinolytic response to venous occlusion is decreased in patients after Kawasaki disease. Blood Coagul Fibrinolysis 2003;14:181 – 6. [25] Noto N, Okada T, Yamasuge M, Taniguchi K, Karasawa K, Ayusawa M, et al. Noninvasive assessment of the early progression of atherosclerosis in adolescents with Kawasaki disease and coronary artery lesions. Pediatrics 2001;107:1095 – 9. [26] Comenzo RL, Malachowski ME, Meissner HC, Fulton DR, Berkman EM. Immune hemolysis, disseminated intravascular coagulation, and serum sickness after large doses of immune globulin given intravenously for Kawasaki disease. J Pediatr 1992;120:926 – 8. [27] Nakamura Y, Yanagawa H, Kato H, Kawasaki T. Mortality rates for patients with a history of Kawasaki disease in Japan. Kawasaki Disease Follow-up Group. J Pediatr 1996;128:75 – 81. [28] Nakamura Y, Yanagawa H, Kato H, Harada K, Kawasaki T. Mortality among patients with a history of Kawasaki disease: the third look. The Kawasaki Disease Follow-up Group. Acta Paediatr Jpn 1998;40:419 – 23. [29] Nakamura Y, Yanagawa H, Harada K, Kato H, Kawasaki T. Mortality among persons with a history of Kawasaki disease in Japan: existence of cardiac sequelae elevated the mortality. J Epidemiol 2000;10:372 – 5. [30] Nakamura Y, Yanagawa H, Harada K, Kato H, Kawasaki T. Mortality among persons with a history of Kawasaki disease in Japan: the fifth look. Arch Pediatr Adolesc Med 2002;156:162 – 5. [31] Dajani AS, Taubert KA, Takahashi M, Bierman FZ, Freed MD, Ferrieri P, et al. Guidelines for long-term management of patients with Kawasaki disease. Report from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 1994;89:916 – 22.
Cardiovascular complications—coronary artery structure and function Brian W. McCrindle* Division of Cardiology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8 Received 5 June 2004; accepted 25 August 2004 Available online 7 October 2004
Abstract During the convalescent phase of Kawasaki disease, structural and functional abnormalities of the coronary and systemic arteries are variably present, and may be independent of the degree of coronary artery involvement during the acute phase of illness. Endothelial dysfunction is the earliest precursor in the development of the atherosclerotic disease process, and its presence and persistence in Kawasaki disease patients remain of concern. In addition, the vascular wall structure is altered in areas of persistent but also possibly bhealedQ involvement. There is concern that these functional and structural abnormalities may lead to accelerated atherosclerosis and earlier manifest cardiovascular disease. These abnormalities raise the possibility that patients who have had Kawasaki disease may merit screening and management of cardiovascular risk factors and ongoing follow-up. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Kawasaki disease; Coronary artery; Endothelium; Myocardial flow reserve
Since the original description of Kawasaki disease, the subsequent 30 years of observation and investigation have led to an increased understanding of the acute and long-term coronary artery complications. Initial descriptions of coronary artery pathology were limited to assessments of the coronary artery lumen as assessed by two-dimensional echocardiography and coronary artery angiography. These studies have given detailed accounts of changes within the lumen of the coronary artery branches in terms of dilatation and aneurysm formation and their regression and resolution. Current definitions of coronary artery involvement rest on the measurement of proximal coronary artery luminal diameters and their degree of deviation from normal based on patient age or body size. The assessment of the coronary artery lumen, however, is a limited indicator of the presence of both functional and structural pathology within the vascular wall. The presence of a normal luminal dimension does not preclude the presence of coronary artery involvement, either in the acute or the convalescent phases. There have been rapid developments in both functional assessment * Tel.: +1 416 813 7610; fax: +1 416 813 7547. E-mail address: [email protected]. 1058-9813/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ppedcard.2004.08.008
and structural imaging of the coronary artery vasculature which have shed new light on the spectrum of coronary artery pathology. In addition, findings from these developments have raised concerns regarding ultra long-term outcome for patients with varying degrees or severity of coronary artery involvement. Of greatest concern is the ongoing question of whether patients who have had either no or minimal and resolved coronary artery involvement are at risk for accelerated atherosclerosis and premature cardiovascular events in their adult years.
1. Coronary artery pathology Given the low mortality associated with Kawasaki disease, the pathology of coronary artery disease and its regression has been described only in limited autopsy studies usually including patients who died with severe coronary artery involvement. Amano et al. [1] described pathological material from 37 autopsied patients. They noted that initial damage to the endothelial cells lead to degeneration and increased vascular permeability and platelet aggregation. This was followed by edema and degeneration of media with
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destruction of smooth muscle cells. Incidentally, they also noted vascular pathology in the venous system as well. Nakatani et al. [2] have recently reported the presence of circulating endothelial cells and endothelial progenitor cells in acute and subacute Kawasaki disease patients, which were more marked in those with coronary artery lesions. Iizuka et al. [3] have noted that abnormally high quantities of nitric oxide were excreted in acute Kawasaki disease patients, which may explain the high prevalence of coronary artery dilation. Fujiwara et al. [4] studied 69 autopsied infants, and noted that a panvasculitis was evident in the acute stages in aneurysmal segments. Healed aneurysmal segments were marked by intimal thickening, although thrombi were also noted with some recanalization. In nonaneurysmal segments, acute inflammation was more localized to the intima and perivascular area of the coronary arteries, followed by less marked intimal thickening. The nature of the acute and convalescent cellular infiltrate has been a focus of study. Koygoku [5] felt that initial seroexudative inflammation was followed by a transient granulocyte-leading stage. This lead to a final lymphocytic interstitial infiltration. Rowley et al. [6] noted early vascular infiltration with IgA plasma cells, and felt that this was evidence for a conventional antigen-driven immune response. Sasaguri and Kato [7] studied five aneurysms from four patients, and noted marked intimal thickening in all. They suggested that thrombosis in the aneurysms had an impact on their fate. Two aneurysms in patients treated with aspirin showed no evidence of thrombosis and a well-regenerated endothelium with marked intimal thickening rich in smooth muscle cells. In contrast, aneurysms in two patients not treated early with aspirin showed massive thrombus formation with calcification as well as intimal thickening. Takahashi et al. [8] studied six autopsy cases. Intimal thickening was noted in nonaneurysmal segments, while thrombotic occlusion occurred in four of six persistent aneurysms, with one patient showing advanced atherosclerotic changes. Those with recanalized aneurysms showed new intimal thickening which progressed to occlusion in some. From this evidence, a picture of the pathology of the coronary arteries can be derived. In the acute phase of Kawasaki disease, there is evidence of endothelial dysfunction and damage, which may be manifest by coronary artery dilation. The pathologic process may also progress to include inflammatory-mediated changes within all layers of the arterial structure. These can lead to weakening and destruction of supportive elements of the vascular wall which, under the presence of hydrostatic forces, can result in aneurysm formation and rarely rupture. Very large aneurysms can represent areas of flow stasis [9] which, together with the presence of endothelial dysfunction and platelet activation, promote the development of thrombosis. These thrombi can be occlusive and may lead to sudden myocardial infarction or they can be laminar along the vessel wall and lead to a reduction in the luminal size. During the convalescent phase, aneurysms tend to heal through progressive intimal prolifer-
ation and neoangiogenesis, which may be mediated by the persistence and extensive expression of vascular growth factors [10]. This may eventually reduce the luminal dimension to a normal size. Nonetheless, these healed aneurysms demonstrate varying thick and stiff vascular walls with persistence of abnormal endothelial function. It is yet unknown but concerning that these alterations in structure and function may lead to an acceleration of the atherosclerotic disease process.
2. Structural imaging New methods have been used to assess the structure of the vascular wall of the coronary arteries. Intravascular ultrasound has been used at the time of cardiac catheterization to assess arterial wall morphology and luminal dimensions in patients who have had Kawasaki disease. Sugimura et al. [11] reported the use of intravascular ultrasound to assess 20 patients, including 10 patients with persistent or regressed aneurysms, 2 patients who had Kawasaki disease but had never had coronary artery involvement, and in 8 normal control subjects. They noted that at sites of regressed aneurysms there was a markedly thickened but smooth intimal surface. Iemura et al. [12] assessed 27 patients more than 10 years after their initial episode of acute Kawasaki disease, including 9 with regressed large aneurysms, 9 with regressed small aneurysms, 4 with both regressed small and large aneurysms, and 5 with no aneurysms. In addition, six normal patients with congenital heart disease were studied as normal controls. In all 27 patients, the coronary artery angiogram showed normal luminal dimensions. Using intravascular ultrasound, they noted that the thickness of the intima-media complex in those with regressed large aneurysms was a mean of 0.59 mm versus 0.29 mm in those with regressed small aneurysms. No abnormalities were noted in segments that had not been previously involved or in the normal control patients. Suzuki et al. [13] used intravascular ultrasound to assess 23 patients at a mean of 11.5 years after Kawasaki disease. The intima-media complex was thickest in those coronary artery segments with regressed aneurysms (mean 0.84 mm) versus those with persistent aneurysms (mean 0.54 mm). Mild thickening was noted in angiographically normal segments (mean 0.22 mm).
3. Functional abnormalities of the coronary arteries The endothelium plays a central role in the regulation of numerous functions of a healthy artery [14]. A healthy endothelium is represented by an intact regulatory smooth antithrombotic, profibrinolytic and anti-inflammatory surface. Many of these functions are mediated through the central role of nitric oxide. These nitric oxide-mediated roles can be impaired through damaging factors that impart an
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oxidative stress. These damaging factors may set in motion the cascade of changes that lead to atherosclerosis, which is a nonspecific vascular healing response. The endothelium can be assessed by its response to various vascular stimuli. Arterial dilation in response to acetylcholine or reactive hyperemia is felt to be mediated through endogenous nitric oxide pathways functioning in a healthy endothelium. Arterial dilation can also be elicited by measuring the vasodilatory response to exogenous nitric oxide, which is felt to be independent of the endothelium. These responses can be assessed invasively in the coronary artery vasculature or noninvasively in superficial arteries. The assessment in superficial systemic arteries does have some correlation to those responses and the presence of disease in the coronary arteries. Mitani et al. [15] used quantitative coronary artery angiography to assess responses to intraluminal infusions of acetylcholine and nitroglycerin. In response to acetylcholine, Kawasaki disease patients had less vasodilation than normal control subjects, regardless of the magnitude of coronary artery involvement. In response to nitroglycerin, vasodilation was least in those with persistent or regressed aneurysms, with those without involvement intermediate relative to normal control subjects. They also assessed reactivity in the superficial femoral arteries, and noted no difference compared to normal control subjects in responses to either reactive hyperemia or nitroglycerin. Likewise, Yamakawa et al. [16] used quantitative angiography to assess responses to acetylcholine in 25 Kawasaki disease patients and 10 normal control subjects. In response to intracoronary infusion, segments with regressed aneurysms showed vasoconstriction, while segments with persistent aneurysms showed no response. Uninvolved segments in Kawasaki disease patients showed similar amounts of vasodilation compared to normal control subjects. The potential clinical relevance of these functional changes can be assessed using positron admission tomography (PET) to quantify myocardial blood flow and myocardial flow reserve in response to provocative maneuvers. Furuyama et al. [17] used PET scanning to study myocardial blood flow in 12 patients with regressed aneurysms in the region of the left anterior descending and in 12 normal control subjects. They noted that while myocardial blood flow at rest was similar in the two groups, in response to adenosine triphosphate, the Kawasaki disease patients had reduced flow, which translated into a reduction in myocardial flow reserve. They likewise had a reduced ratio myocardial blood flow at rest versus with cold pressor testing versus the normal controls. They concluded that there was impaired myocardial blood flow and that endothelial dysfunction was present in the area of the regressed aneurysms. A further study by Furuyama et al. [18] showed that myocardial flow reserve was most reduced in regions distal to a stenosis (Fig. 1). Regions supplied by arteries with either persistent or regressed coronary aneurysms also had less marked reductions in myocardial flow reserve. Areas
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Fig. 1. Impaired myocardial flow reserve in coronary artery segments with varying degrees of involvement after Kawasaki disease compared to a normal control group. Compared to normals, all myocardial regions in the Kawasaki disease patients had reduced reserve, significantly lower in areas supplied by a stenotic coronary artery segment. Adapted from Furuyama et al. [18].
supplied by segments that had never been involved also showed reductions in myocardial flow reserve in comparison to normal control subjects. Regardless of the level of coronary artery involvement the change in myocardial blood flow with cold pressor stress was reduced in all segments compared to the normal controls. Muzik et al. [19] also quantified myocardial blood flow and flow reserve using PET scanning in Kawasaki disease patients. They studied 10 children with a history of Kawasaki disease and 10 healthy adult controls. The study was unique in that none of the Kawasaki disease patients had had any luminal changes during the acute or convalescent stages. Myocardial blood flow at rest was similar in both patient and control groups. However, in response to hyperemic blood flow induced by adenosine stress, the myocardial blood flow was significantly lower in the Kawasaki disease patients, with lower estimates of myocardial flow reserve and higher total coronary resistance (Fig. 2). A quantitative analysis of perfusion images demonstrated no evidence of regional perfusion abnormalities in either study group. They concluded that these patients had impaired vasodilatory capacity and that damage might reside in the coronary artery microcirculation. Hauser et al. [20] likewise studied myocardial blood flow and flow reserve using PET scanning. They studied 10 patients with Kawasaki disease who all had an initial aneurysm in their coronary arteries with complete resolution during follow-up. They compared them to 10 normal control subjects and noted that myocardial blood flow at rest was similar in the two groups but impaired in response to provocation with adenosine stress with reduced coronary flow reserve. Again, no stress-induced perfusion defects were noted. A relationship between structural and functional changes has been defined. Iemura et al. [12] also assessed coronary artery function as part of their study of intravascular
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Fig. 2. Impaired myocardial blood flow and flow reserve in coronary arteries assessed by positron emission tomography in Kawasaki disease patients with no history of coronary artery involvement. Myocardial blood flow in response to adenosine-induced vasodilation was significantly lower in the patients versus healthy adult controls ( p=0.01) with lower myocardial flow reserve ( p=0.003). Adapted from Muzik et al. [19].
ultrasound. Using intraluminal infusions of nitroglycerine, they assessed arterial vasodilatation as a measure of an endothelium-independent response. They noted that vasodilatation was most reduced in those with segments with regressed large aneurysms, followed by those with regressed small aneurysms with those segments having no structural abnormalities and in the normal controls showing normal amounts of vasodilatation. They also assessed vasodilatation in response to acetylcholine, which is a measure of endothelium-dependent response. They noted that in those segments with regressed large aneurysms there was marked vasoconstriction with a lesser degree of vasoconstriction in those segments with regressed small aneurysms. In those segments assumed to be normal, there was significantly less vasodilatation than that seen in those of the normal control subjects. Similar findings were noted in the intravascular ultrasound study by Suzuki et al. [13]. These studies therefore suggest that in areas of healed aneurysms there is considerable stiffness of the vascular wall with markedly abnormal function of the endothelium. In those segments presumed to have had no coronary artery involvement, while there does not appear to be excessive stiffness, some element of endothelial dysfunction may be present. Nonetheless, these functional changes did not translate into any abnormalities regarding perfusion. The relevance in terms of an increased risk for acceleration of the atherosclerotic disease process is as yet unknown.
on assessments of endothelial dysfunction in both the coronary artery vasculature and the systemic arterial bed. Dhillon et al. [21] used vascular ultrasound to study reactivity in the brachial artery. They studied 20 patients at a median of 11 years after their acute Kawasaki disease episode, and compared them to results in 20 age- and gender-matched controls. They noted no differences in baseline lipid profile values. In response to reactive hyperemia, a measure of endothelium-dependent vasomotion, they noted a mean dilatation of 3.1% in the Kawasaki disease patients versus 9.4% in the control subjects, a difference that was statistically significant. In response to sublingual glyceryl trinitrate, a measure of endotheliumindependent vasomotion, the mean amount of dilatation was 23% in the patients versus 21.7% in the controls. This study suggested that endothelial dysfunction is present, possibly throughout the systemic arterial bed, in patients who have had Kawasaki disease. These results are in contrast to those of Silva et al. [22] who, in a similar case-control study, noted no significant differences in either flow-mediated or nitroglycerine-mediated vasodilatation in the brachial artery of the Kawasaki disease patients. They did assess numerous other cardiovascular risk factors for atherosclerosis and did note some significant differences. Deng et al. [23] assessed 39 patients at a mean of 7.1 years after their Kawasaki disease episode, and compared them to 17 age- and gender-matched control subjects. They noted abnormalities in flow-mediated but not nitroglycerinemediated brachial artery reactivity in the Kawasaki disease patients. They then gave half of the Kawasaki disease patients an intravenous dose of vitamin C and noted that the flow-mediated dilatation improved to near normal (Fig. 3). This would suggest that the use of antioxidant vitamin, vitamin C, reduced oxidative stress that may be present in patients after Kawasaki disease and improved endothelial function.
4. Are Kawasaki disease patients at increased risk for accelerated or premature atherosclerosis? There has been some debate whether having had Kawasaki disease confers an added risk for premature or accelerated atherosclerosis. Much of this debate has focused
Fig. 3. Improved endothelial function of the brachial artery after infusion of vitamin C in Kawasaki disease patients. Endothelium-dependent vasodilation as provoked by reactive hyperemia was reduced in Kawasaki disease patients but improved significantly with an intravenous administration of vitamin C. Adapted from Deng et al. [23].
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has been increasing in the Kawasaki disease cohort with successively longer follow-up, the overall standardized mortality ratio continues to fall. It is higher for males than for females, and the increase seems to be most marked in those males within the first 2 months of the acute episode or in males with cardiac involvement. The fact that the standardized mortality ratio continues to decrease with progressive follow-up suggests that these patients have not yet manifest any evidence for premature mortality.
5. Summary
Fig. 4. Greater intima-media thickness with greater stiffness of the carotid arteries after Kawasaki disease. Adapted from Noto et al. [25].
Albisetti et al. [24] studied 42 patients in the convalescent phase after acute Kawasaki disease, 22 of whom had never had any luminal abnormalities of their coronary arteries. They compared the results to 26 age- and gendermatched control subjects, and used venous occlusion stress testing to assess fibrinolytic capacity as a measure of endothelial function. At baseline, they noted that the patients had higher fibrinogen, plasminogen, and alpha-2 macroglobulin levels. The Kawasaki disease patients showed a decreased fibrinolytic response to the stress testing with a decrease in tissue plasminogen activator antigen. These abnormalities were not related to the degree of coronary artery luminal changes. Vascular ultrasound can also be used to assess structural changes that may be indicative of early progression of atherosclerosis. These are usually assessed in the carotid arteries by measuring the thickness of the intima-media complex. Noto et al. [25] assessed 20 patients who had had coronary artery lesions after Kawasaki disease and compared them to 20 age- and gender-matched controls (Fig. 4). They found no difference in baseline lipid profile values, blood pressure or body mass index, although the Kawasaki disease patients were noted to have a higher hemoglobin A1c levels. From carotid artery ultrasound, they noted that the Kawasaki disease patients had a slight but statistically significant increase in the thickness of the intima-media complex, and a more marked increase in the stiffness index of the carotid arteries, suggesting the presence of early systemic vascular changes. In light of these structural and functional changes in both the coronary arterial and systemic arterial beds, concerns will linger as to whether these patients will have a future of premature atherosclerotic cardiovascular disease. Unfortunately, follow-up of Kawasaki disease patients has not yet been sufficiently long to determine if this is apparent. Nakamura et al. have been following a cohort of Kawasaki disease patients assembled from 1982 to 1992 in Japan, and comparing their mortality to that of a similar age- and gender-matched cohort [26–30]. While the number of deaths
Structural and functional abnormalities of the coronary and systemic arteries are present in patients in the convalescent phase of Kawasaki disease, and may be independent of the degree of initial coronary artery involvement as noted by assessment of the vascular lumen. Endothelial dysfunction is the earliest precursor in the development of the atherosclerotic disease process, and its presence and persistence in Kawasaki disease patients remain of concern. It is controversial how this should be addressed in the long-term follow-up and management of Kawasaki disease patients with varying degrees of initial and regressed or resolved coronary artery involvement [31]. As a minimum, patients who have had Kawasaki disease should be counseled as to cardiovascular risk factors for atherosclerosis and their reduction. Controversial areas include whether Kawasaki disease patients should be screened for all known cardiovascular risk factors, and whether patients who have had no coronary artery involvement or only transient dilatation that resolved should require long-term cardiology follow-up and evaluation. Clear evidence is needed to address this controversy.
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