Letter to the Editor

Statin reduces persistent coronary arterial inflammation evaluated by serial ¹⁸fluorodeoxyglucose positron emission tomography imaging long after Kawasaki disease

HMG-CoA reductase inhibitors, or statins, are potent plasma LDL-cholesterol (LDL-c) lowering agents. Since the introduction of the first statin, lovastatin, in 1987, accumulating evidence showed that non-cholesterol lowering effects play an important role in their efficacy to reduce atherosclerotic cardiovascular disease (ASCVD). Thus, these non-LDL-c lowering properties could benefit patients with immune-mediated diseases. Statins and their associated immune-modulating roles have recently received much attention. Different statins have been administered in various experimental and clinical studies focused on autoimmunity. The results indicate that statins can modulate immune responses through mevalonate pathway-dependent and -independent mechanisms. The anti-inflammatory and immune-modulating effects include cell adhesion, migration of antigen presenting cells, and differentiation, as well as activation, of T-cells. In various autoimmune diseases (e.g. rheumatoid arthritis, lupus, and multiple sclerosis), promising results have been obtained to date.

Together with heart-healthy lifestyle habits, statins serve as the cornerstone of primary and secondary prevention of atherosclerotic cardiovascular disease in adults. Several conditions, most notably familial hypercholesterolemia (FH), cause early dyslipidemia and vascular disease, contributing to the development and progression of atherosclerosis from childhood and increased cardiovascular risk. In recent decades, studies increasingly have evaluated the safety and efficacy of statins in such high-risk youth. The strongest evidence for pediatric statin use is for the heterozygous FH population, whereby statin use has been shown to lower low-density lipoprotein cholesterol effectively, slow the progression of atherosclerosis and vascular dysfunction, and significantly reduce cardiovascular risk in early adulthood. Numerous meta-analyses and Cochrane reviews have demonstrated that attributed adverse effects, including liver toxicity, myositis, and rhabdomyolysis, occur no more frequently in youth receiving statins than placebos, with no impact on growth or development. However, further studies evaluating the long-term safety of pediatric statin use are required. In the current review, we summarize the pediatric experience of statin use to date, focusing on its utility for FH, Kawasaki disease, post-heart transplantation, and other at-risk populations. Current guidelines and indications for use are summarized, and the short- and medium-term safety experience is reviewed. Finally, a clinical approach to the indications, initiation, and monitoring of statins in youth is provided.

Conjointement aux habitudes de vie favorables à la santé cardiovasculaire, les statines représentent la pierre angulaire de la prévention primaire et secondaire de la maladie cardiovasculaire athérosclérotique chez les adultes. Plusieurs maladies, plus particulièrement l’hypercholestérolémie familiale (HF), causent précocement une dyslipidémie et une maladie vasculaire, qui contribuent au développement et à la progression de l’athérosclérose de l’enfance et un risque cardiovasculaire accru. Au cours des dernières décennies, les études portaient de plus en plus sur l’évaluation de l’innocuité et de l’efficacité des statines chez les jeunes exposés à ce risque élevé. Les preuves les plus solides sur l’utilisation des statines en pédiatrie sont celles des populations hétérozygotes atteintes de HF, chez qui l’utilisation des statines a démontré abaisser efficacement les lipoprotéines de faible densité, ralentir la progression de l’athérosclérose et la dysfonction vasculaire, en plus de réduire significativement le risque cardiovasculaire au début de l’âge adulte. De nombreuses méta-analyses et revues Cochrane ont démontré que les effets défavorables qui y sont attribués sont entre autres l’hépatotoxicité, la myosite et la rhabdomyolyse, qui ne surviennent pas plus fréquemment chez les jeunes qui reçoivent des statines que chez ceux qui reçoivent les placebos, et qu’elles n’ont pas de répercussions sur la croissance ou le développement. Toutefois, des études plus poussées qui porteront sur l’évaluation de l’innocuité à long terme de l’utilisation des statines en pédiatrie sont nécessaires. Dans la revue actuelle, nous résumons l’expérience de l’utilisation des statines en pédiatrie jusqu’à ce jour et nous nous penchons principalement sur son utilité lors de HF, de la maladie de Kawasaki, de la post-transplantation cardiaque et sur d’autres populations exposées au risque. Nous résumons les lignes directrices actuelles et les indications quant à leur utilisation et passons en revue l’expérience sur l’innocuité à court et à moyen terme. Finalement, nous proposons une approche clinique en matière d’indications, d’introduction et de surveillance des statines chez les jeunes.

To determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of a 6-week course of atorvastatin in patients with acute Kawasaki disease with coronary artery (CA) aneurysm (CAA).

This was a Phase I/IIa 2-center dose-escalation study of atorvastatin (0.125-0.75 mg/kg/day) in 34 patients with Kawasaki disease (aged 2-17 years) with echocardiographic evidence of CAA. We measured levels of the brain metabolite 24(S)-hydroxycholesterol (24-OHC), serum lipids, acute-phase reactants, liver enzymes, and creatine phosphokinase; peripheral blood mononuclear cell populations; and CA internal diameter normalized for body surface area before atorvastatin treatment and at 2 and 6 weeks after initiation of atorvastatin treatment.

A 6-week course of up to 0.75 mg/kg/day of atorvastatin was well tolerated by the 34 subjects (median age, 5.3 years; IQR, 2.6-6.4 years), with no serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported in adults, suggesting a slower rate of metabolism in children. The 24-OHC levels were similar between the atorvastatin-treated subjects and matched controls.

Atorvastatin was safe and well tolerated in our cohort of children with acute Kawasaki disease and CAA. A Phase III efficacy trial is warranted in this patient population, which may benefit from the known anti-inflammatory and immunomodulatory effects of this drug.

Accurate cardiovascular imaging is essential for the successful management of patients with congenital heart disease (CHD). Echocardiography and angiography have been for long time the most important imaging modalities in pediatric cardiology, but nuclear medicine has contributed in many situations to the comprehension of physiological consequences of CHD, quantifying pulmonary blood flow symmetry or right-to-left shunting. In recent times, remarkable improvements in imaging equipments, particularly in multidetector computed tomography and magnetic resonance imaging, have led to the progressive integration of high resolution modalities in the clinical workup of children affected by CHD, reducing the role of diagnostic angiography. Technology has seen a parallel evolution in the field of nuclear medicine, with the advent of hybrid machines, as SPECT/CT and PET/CT scanners. Improved detectors, hugely increased computing power, and new reconstruction algorithms allow for a significant reduction of the injected dose, with a parallel relevant decrease in radiation exposure. Nuclear medicine retains its distinctive capability of exploring at the tissue level many functional aspects of CHD in a safe and reproducible way. The lack of invasiveness, the limited need for sedation, the low radiation burden, and the insensitivity to body habitus variations make nuclear medicine an ideal complement of echocardiography. This is particularly true during the follow-up of patients with CHD, whose increasing survival represent a great medical success and a challenge for the health system in the next decades. Metabolic imaging using ¹⁸FDG PET/CT has expanded its role in the management of infection and inflammation in adult patients, particularly in cardiology. The same expansion is observed in pediatric cardiology, with an increasing rate of studies on the use of FDG PET for the evaluation of children with vasculitis, suspected valvular infection or infected prosthetic devices. The introduction in the clinical practice of the first integrated PET/MR scanners and the development of new radiopharmaceuticals, as fluorinated compounds for the study of myocardial perfusion, open new perspectives in the use of nuclear medicine techniques in pediatric cardiology, offering the potential of a detailed noninvasive morphofunctional characterization in many types of CHD.