Lesnik Oberstein Saskia A J, Jukema J Wouter, Van Duinen Sjoerd G, Macfarlane Peter W, van Houwelingen Hans C, Breuning Martijn H, Ferrari Michel D, Haan Joost
Department of Clinical Genetics, Leiden University Medical Center, The Netherlands.
Medicine (Baltimore). 2003 Jul;82(4):251-6. doi: 10.1097/01.md.0000085054.63483.40.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an angiopathy caused by mutations in the NOTCH3 gene. Typical microvascular changes are found throughout the arterial tree, but the documented disease expression is confined to the central nervous system. In an ongoing CADASIL study, we noted a number of patients with early acute myocardial infarction (before the age of 50 years), as well as patients with electrocardiogram (ECG) abnormalities. We analyzed these data to determine whether myocardial ischemia is associated with NOTCH3 mutations. ECGs were recorded in mutated (n = 41) and nonmutated (n = 22) individuals from 15 genetically confirmed CADASIL families, and blindly classified according to the Minnesota code. Cardiologic history was assessed and cardiovascular disease risk factors were determined. Evidence for myocardial infarction was defined as a positive history for acute myocardial infarction and/or a Minnesota Code 1 (Q-waves) on ECG. We examined CADASIL myocardial tissue ultrastructurally and immunohistochemically for evidence of microangiopathy. We found that almost 25% (10/41) of mutation carriers had evidence of myocardial infarction, versus none of the 22 nonmutation carriers (p = 0.011). Five had a medical history of acute myocardial infarction, and 5 had current pathologic Q-waves on ECG. Acute myocardial infarction occurred at a mean age of 39.6 +/- 5.22 years, and predated major neurologic symptoms of CADASIL in all cases. Pathologic examination of myocardial tissue revealed typical CADASIL arteriopathic changes of the coronary microvasculature. To our knowledge, this is the first study showing that NOTCH3 mutation carriers may be at increased risk of early acute myocardial infarction, expanding CADASIL disease expression beyond the central nervous system to include the heart.
伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）是一种由NOTCH3基因突变引起的血管病。典型的微血管变化可见于整个动脉系统，但已记录的疾病表现仅限于中枢神经系统。在一项正在进行的CADASIL研究中，我们注意到一些患有早期急性心肌梗死（50岁之前）的患者以及有心电图（ECG）异常的患者。我们分析了这些数据，以确定心肌缺血是否与NOTCH3突变有关。对来自15个经基因确诊的CADASIL家系的突变个体（n = 41）和非突变个体（n = 22）进行了心电图记录，并根据明尼苏达编码进行盲法分类。评估了心脏病史并确定了心血管疾病危险因素。心肌梗死的证据定义为急性心肌梗死的阳性病史和/或心电图上的明尼苏达编码1（Q波）。我们对CADASIL心肌组织进行了超微结构和免疫组织化学检查，以寻找微血管病的证据。我们发现，近25%（10/41）的突变携带者有心肌梗死的证据，而22名非突变携带者均无（p = 0.011）。5人有急性心肌梗死病史，5人目前心电图上有病理Q波。急性心肌梗死发生的平均年龄为39.6 +/- 5.22岁，且在所有病例中均早于CADASIL的主要神经症状出现。心肌组织的病理检查显示冠状动脉微血管有典型的CADASIL动脉病变。据我们所知，这是第一项表明NOTCH3突变携带者可能有早期急性心肌梗死风险增加的研究，将CADASIL的疾病表现扩展到中枢神经系统之外，包括心脏。
