Successful PCI for advanced coronary stenoses of a generalized arterial calcification of infancy (GACI) survivor

Generalized arterial calcification of infancy (GACI) is an extremely rare condition characterized by widespread arterial calcification within the first month of life and stenosis of large and medium-sized arteries. It is primarily caused by mutations in ENPP1 (70%–75% of cases) or ABCC6 (~10%), leading to reduced serum pyrophosphate (PPi) levels, a critical inhibitor of calcification. GACI has a high mortality rate, with 55% of affected infants dying before 6 months and 24.4% lost in utero.1 Information on long-term prognosis is limited. Here, we report the first case of a GACI survivor who successfully underwent percutaneous coronary intervention (PCI) for advanced right coronary artery (RCA) stenosis at age 14. A male infant, born at 41 weeks of gestation and weighing 3092 g, urgently entered the NICU on day two for acute respiratory failure. He had hypertension accompanied by elevated plasma renin activity and aldosterone levels, leading to a diagnosis of renovascular hypertension, which progressed to hypertensive heart failure. A plain CT imaging showed widespread arterial calcifications involving the coronary, splenic, renal, intestinal, femoral, and peripheral arteries, raising suspicion for GACI. He was treated with bisphosphonates to inhibit calcification and ACE inhibitors to manage the renovascular hypertension. As a result, arterial calcification was resolved within 6 months, but hypertension and increased renin activity persisted. At age three, cardiac catheterization revealed mild stenoses in the RCA. Genetic testing at age 12 years identified heterozygous variants in the ABCC6 gene (c.1256G>A, p. R419Q and c.595C>T, pQ199*), confirming GACI2. At age 14, he developed exercise-induced fatigue (NYHA class II). Although the exercise stress ECG showed no ST changes, myocardial scintigraphy using Technetium-99m sestamibi under pharmacologic stress revealed ischemic changes in the inferior left ventricle. Coronary angiography showed severe multiple stenoses in the RCA segments 1, 2, and 3 (Figure 1a), while the left coronary artery remained intact. Intravascular ultrasound (IVUS) and optical frequency domain imaging (OFDI) demonstrated calcification spread over the internal elastic lamina of the RCA, involving both stenotic and non-stenotic lesions (Figure 1c–f). PCI was performed to improve RCA perfusion. Given the patient's young age and the associated risk of stent thrombosis and long-term dual antiplatelet therapy, all stenoses in RCA segments 1, 2, and 3 were dilated using drug-coated balloons (DCBs). There were no complications associated with PCI. Postoperatively, he received dual antiplatelet therapy with aspirin and prasugrel for 3 months, followed by aspirin monotherapy. Follow-up angiography at 3 months showed improved RCA perfusion with no evidence of restenosis in any segment (Figure 1b). Clinically, his exercise-induced fatigue resolved, and his NYHA score improved to class I. Post-PCI scintigraphy confirmed resolution of inferior ischemia. GACI has been classified into early- and late-onset types based on the time of initial presentation.1 Early-onset cases manifest in utero or within the first week with fetal distress (46%), heart failure (44%), polyhydramnios (38%), hypertension (33%), and respiratory distress (30%). Late-onset cases present in infancy with respiratory distress (66%), cyanosis (43%), and feeding difficulty (34%). This patient case represents an early-onset GACI, presenting within the first week of life. While early-onset GACI is often associated with a poor prognosis, arterial calcifications can regress spontaneously in some cases.2 Survivors require long-term monitoring and individualized treatment. GACI is caused by pathogenic variants in ENPP1(GACI1) or ABCC6(GACI2), the latter implicated in the etiopathogenesis of pseudoxanthoma elasticum (PXE), a disorder with elastic tissue calcification affecting skin, eyes, and blood vessels. Clinical features of PXE include distinctive dermal papules, angioid streaks in the retina, and vascular complications such as coronary artery disease. Some GACI survivors develop PXE-like coronary lesions.3 The overlapping pathogenesis is due to reduced PPi levels, leading to ectopic calcification. In this patient, the coronary artery lesions exhibited features similar to those observed in PXE, such as calcification of the internal elastic lamina and arterial narrowing.4 ENPP1 hydrolyzes extracellular ATP into PPi and AMP, while ABCC6 facilitates ATP transport for PPi production. Loss-of-function mutations disrupt these pathways, promoting vascular calcification.5 Histologically, GACI-related coronary lesions show internal elastic lamina calcification and arterial narrowing, as observed in PXE. To the best of our knowledge, this is the first reported case of PCI in a GACI survivor. PCI has rarely been reported, even in PXE patients, despite coronary artery disease being a recognized complication.4 Unlike atherosclerotic disease, dominated by intimal plaque, GACI lesions are rigid and circumferentially calcified along the internal elastic lamina, which may limit the effectiveness of plain old balloon angioplasty (POBA). In this case, multimodality intravascular imaging defined diffuse but focally elastic-lamina calcification with moderate plaque only at stenosis sites and supported a stent-less strategy using DCBs to avoid long-term stent-related complications in a young patient. The success of stent-less PCI in this patient highlights its feasibility and potential as a therapeutic option for managing severe coronary stenosis in GACI survivors. A.T. and Y.N. wrote the main manuscript text and prepared figures. Y.N. gave technical support and conceptual advice. T.H. and K.Y. critically reviewed the manuscript. All authors read and approved the final manuscript. Written informed consent was obtained from the patient‘s parents for the publication of this case report and accompanying images. The authors thank Dr. Nobuaki Ito for helpful comments and genetic testing. We also thank Dr. Tetsuya Matoba for useful discussions and technical assistance. The authors declare no conflicts of interest related to this article. The data that support the findings of this study are available from the corresponding author upon reasonable request.