Environmental epidemiology of Kawasaki disease: Linking disease etiology, pathogenesis and global distribution.

BACKGROUND: The pathogenesis of Kawasaki disease (KD) is commonly ascribed to an exaggerated immunologic response to an unidentified environmental or infectious trigger in susceptible children. A comprehensive framework linking epidemiological data and global distribution of KD has not yet been proposed. METHODS AND FINDINGS: Patients with KD (n = 81) were enrolled within 6 weeks of diagnosis along with control subjects (n = 87). All completed an extensive epidemiological questionnaire. Geographic localization software characterized the subjects' neighborhood. KD incidence was compared to atmospheric biological particles counts and winds patterns. These data were used to create a comprehensive risk framework for KD, which we tested against published data on the global distribution. Compared to controls, patients with KD were more likely to be of Asian ancestry and were more likely to live in an environment with low exposure to environmental allergens. Higher atmospheric counts of biological particles other than fungus/spores were associated with a temporal reduction in incidence of KD. Finally, westerly winds were associated with increased fungal particles in the atmosphere and increased incidence of KD over the Greater Toronto Area. Our proposed framework was able to explain approximately 80% of the variation in the global distribution of KD. The main limitations of the study are that the majority of data used in this study are limited to the Canadian context and our proposed disease framework is theoretical and circumstantial rather than the result of a single simulation. CONCLUSIONS: Our proposed etiologic framework incorporates the 1) proportion of population that are genetically susceptible; 2) modulation of risk, determined by habitual exposure to environmental allergens, seasonal variations of atmospheric biological particles and contact with infectious diseases; and 3) exposure to the putative trigger. Future modelling of individual risk and global distribution will be strengthened by taking into consideration all of these non-traditional elements.

Cardiac macrophages and apoptosis after myocardial infarction: effects of central MR blockade.

After myocardial infarction (post-MI), inflammation and apoptosis contribute to progressive cardiac remodeling and dysfunction. Cardiac mineralocorticoid receptor (MR) and ß-adrenergic signaling promote apoptosis and inflammation. Post-MI, MR activation in the brain contributes to sympathetic hyperactivity and an increase in cardiac aldosterone. In the present study, we assessed the time course of macrophage infiltration and apoptosis in the heart as detected by both terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and active caspase-3 immunostaining in both myocytes and nonmyocytes, as well as the effects of central MR blockade by intracerebroventricular infusion of eplerenone at 5 µg/day on peak changes in macrophage infiltration and apoptosis post-MI. Macrophage numbers were markedly increased in the infarct and peri-infarct zones and to a minor extent in the noninfarct part of the left ventricle at 10 days post-MI and decreased over the 3-mo study period. Apoptosis of both myocytes and nonmyocytes was clearly apparent in the infarct and peri-infarct areas at 10 days post-MI. For TUNEL, the increases persisted at 4 and 12 wk, but the number of active caspase-3-positive cells markedly decreased. Central MR blockade significantly decreased CD80-positive proinflammatory M1 macrophages and increased CD163-positive anti-inflammatory M2 macrophages in the infarct. Central MR blockade also reduced apoptosis of myocytes by 40-50% in the peri-infarct and to a lesser extent of nonmyocytes in the peri-infarct and infarct zones. These findings indicate that MR activation in the brain enhances apoptosis both in myocytes and nonmyocytes in the peri-infarct and infarct area post-MI and contributes to the inflammatory response.

Brain renin-angiotensin-aldosterone system and ventricular remodeling after myocardial infarct: a review.

After a myocardial infarct (MI), a variety of mechanisms contribute to progressive cardiac remodeling and dysfunction. Progressive activation of central sympathoexcitatory pathways appears to depend on a neuromodulatory pathway, involving local production of aldosterone and release of endogenous ouabain-like compounds ('ouabain') possibly from magnocellular neurons in the supraoptic and paraventricular nuclei. 'Ouabain' may lower the membrane potential of neurons and thereby enhance activity of angiotensinergic pathways. These central pathways appear to coordinate progressive activation of several peripheral mechanisms such as sympathetic tone and circulating and cardiac renin-angiotensin-aldosterone system (RAAS). Central blockade of aldosterone production, mineralocorticoid receptors, 'ouabain' activity, or AT1 receptors similarly prevents activation of these peripheral mechanisms. Cardiac remodeling after MI involves progressive left ventricular dilation, fibrosis, and decrease in contractile performance. Central blockade of this neuromodulatory pathway causes a marked attenuation of the remodeling and dysfunction, presumably by inhibiting increases in (cardiac) sympathetic activity and RAAS. At the cellular level, these systems may contribute to the cardiac remodeling by activating proinflammatory cytokines and cardiac myocyte apoptosis. New therapeutic approaches, specifically preventing activation of this brain neuromodulatory pathway, may lead to more optimal and specific approaches to the prevention of heart failure after MI.