BRCA1 tumours correlate with a HIF-1α phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression

BACKGROUND: There are limited data regarding the hypoxia pathway in familial breast cancers. We therefore performed a study of hypoxic factors in BRCA1, BRCA2 and BRCAX breast cancers. METHODS: Immunoperoxidase staining for HIF-1alpha, PHD1, PHD2, PHD3, VEGF and FIH was carried out in 125 (38 BRCA1, 33 BRCA2 and 54 BRCAX) breast carcinomas. These were correlated with clinicopathological parameters and the intrinsic breast cancer phenotypes. RESULTS: BRCA1 tumours correlated with positivity for HIF-1alpha (P=0.008) and negativity for PHD3 (P=0.037). HIF-1alpha positivity (P=0.001), PHD3 negativity (P=0.037) and nuclear FIH negativity (P=0.011) was associated with basal phenotype. HIF-1alpha expression correlated with high tumour grade (P=0.009), negative oestrogen receptor (ER) status (P=0.001) and the absence of lymph node metastasis (P=0.028). Nuclear FIH expression and PHD3 correlated with positive ER expression (P=0.024 and P=0.035, respectively). BRCA1 cancers with positive HIF-1alpha or cytoplasmic FIH had a significantly shorter relapse-free survival (P=0.007 and P=0.049, respectively). CONCLUSIONS: The aggressive nature of BRCA1 and basal-type tumours may be partly explained by an enhanced hypoxic drive and hypoxia driven ER degradation because of suppressed PHD and aberrantly located FIH expression. This may have important implications, as these tumours may respond to compounds directed against HIF-1alpha or its downstream targets

Frequency of coronary artery stenosis in patients with asymptomatic familial hypercholesterolemia and its association with carotid intimal thickness and cardio-ankle vascular index [Corrigendum]

Suzuki M, Takahashi M, Iizuka T et al. Frequency of coronary artery stenosis in patients with asymptomatic familial hypercholesterolemia and its association with carotid intimal thickness and cardio-ankle vascular index. Research Reports in Clinical Cardiology. 2016;7:83–90. Read the original articl

Effect of nitroglycerin administration on cardio-ankle vascular index

Kazuhiro Shimizu,1 Tomoyuki Yamamoto,2,3 Mao Takahashi,1 Shuji Sato,1 Hirofumi Noike,1 Kohji Shirai2 1Department of Internal Medicine, 2Department of Vascular Function, Toho University Sakura Medical Center, Chiba, 3Biological Information Analysis Section, Fukuda Denshi Co., Ltd, Tokyo, Japan Purpose: The purpose of this study was to clarify the difference between effects of nitroglycerin (NTG) on the functional stiffness in patients with and without coronary artery disease (CAD) using a newly developed stiffness index, cardio-ankle vascular index (CAVI).Subjects and methods: The two subject groups in this study were normal controls (n=31) and CAD patients (n=25). The normal controls had no medical history and were not on regular medications. On the other hand, the CAD patients had received various treatments like antihypertensive drugs, hypoglycemic agents, and statins. This study was conducted in CAD patients under medications. After a single sublingual administration of NTG 0.3 mg, CAVI, blood pressure (BP), and heart rate (HR) were measured every 5 minutes for 20 minutes. Comparisons of each parameter before and after taking NTG were evaluated for statistical significance using analysis of variance and post hoc tests. Tukey–Kramer test was used for post hoc comparisons.Results: In the normal controls, CAVI significantly decreased from baseline after 5, 10, and 15 minutes (from 6.5±0.9 to 5.2±0.9, 5.5±0.9, and 5.7±0.9, respectively). Systolic BP and HR were not significantly changed. Diastolic BP significantly decreased from baseline after 5 and 10 minutes (from 72±8 to 64±9 and 63±9 mmHg, respectively). On the other hand, CAVI, HR, and diastolic BP were not changed significantly in CAD patients. Systolic BP was significantly decreased from baseline after 5, 10, and 15 minutes (from 147±16 to 131±14, 129±12, and 129±13 mmHg, respectively). In the comparison of the two groups, ΔCAVI was not significantly different between the normal controls and CAD patients (–1.4±0.7 vs –1.4±0.9, –1.1±0.7 vs –1.4±1.0, –0.8±0.7 vs –1.2±1.0, and –0.5±0.7 vs –1.1±1.0 at 5, 10, 15, and 20 minutes, respectively). ΔHR was not significantly different between the two groups. ΔSystolic BP in the CAD patients was significantly higher than in the normal controls at 5, 10, 15, and 20 minutes (normal controls vs CAD; –3±7 vs –10±11, –3±5 vs –10±11, –3±6 vs –13±10, and –1±6 vs –11±10 mmHg, respectively). ΔDiastolic BP in the normal controls was significantly higher than in the CAD patients at 5 and 10 minutes (normal controls vs CAD; –8±6 vs –4±4 and –9±4 vs –6±5 mmHg, respectively). Conclusion: After NTG administration, the stiffness of the arteries from the origin of the aorta to the ankle as measured by CAVI decreased in both the normal controls and CAD patients, indicating that the response of arterial smooth muscle cells to nitric oxide is preserved even in CAD patients under medication. Keywords: arterial stiffness, cardio-ankle vascular index, nitroglycerin, nitric oxide, stiffness paramete

Frequency of coronary artery stenosis in patients with asymptomatic familial hypercholesterolemia and its association with carotid intimal thickness and cardio-ankle vascular index

Masayo Suzuki,1 Mao Takahashi,1 Takuo Iizuka,1 Hitoshi Terada,2 Hirohumi Noike,1 Kohji Shirai3 1Cardiovascular Center, Internal Medicine, 2Department of Radiology, 3Department of Vascular Function, Sakura Hospital, Medical Center, Toho University, Sakura City, Chiba Prefecture, Japan Background: Familial hypercholesterolemia (FH) is associated with premature coronary arterial disease. We aimed to determine the incidence of coronary artery stenosis (CAS) in asymptomatic FH patients using coronary computed tomography angiography (CCTA). To investigate the association between CAS and atherosclerosis of carotid arteries, we performed ultrasonography to measure the mean intima-media thickness (IMT), maximum IMT, and plaque score. We also aimed to examine the significance of the cardio-ankle vascular index (CAVI) and its association with the incidence of CAS in asymptomatic FH patients. Patients and methods: We enrolled consecutively, 31 FH patients without symptoms of coronary artery disease. Based on the CCTA findings, we divided the patients into two groups, those with and without CAS, and compared various parameters and risk factors of the two groups. Results: Of 31 FH patients, seven patients (22.6%) had CAS. The proportion of male patients and mean low-density lipoprotein-cholesterol level were higher in patients with CAS than in those without CAS (P<0.05). All carotid ultrasonography parameters (ie, mean IMT, maximum IMT, and plaque score) were significantly higher in patients with CAS than in those without CAS (P<0.01), whereas no significant difference was found in CAVI between the two groups. Conclusion: CAS was identified in >22.6% of the asymptomatic FH patients. Patients with CAS tended to have enhanced levels of carotid plaque markers, but no increase was noted in CAVI. FH patients should be continuously monitored using CCTA and ultrasonography. Keywords: CAVI, coronary artery stenosis, heterozygous familial hypercholesterolemia, CCTA, ultrasound evaluation of the carotid arter