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Yuki Ikeda,1 Masahiro Iwakawa,1 Hajime Kiyokawa,1 Takahiro Nakagami,1 Shinya Kanzaki,2 Akihiro Ogawa,2 Tsuyoshi Tabata,3 Mao Takahashi,1 Toshio Kinoshita,1,3 Kazuhiro Shimizu1 1Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan; 2Department of Rehabilitation, Toho University Sakura Medical Center, Chiba, Japan; 3Department of Clinical Functional Physiology, Toho University Sakura Medical Center, Chiba, JapanCorrespondence: Kazuhiro Shimizu, Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan, Tel +81-43-462-8811, Fax +81-43-462-8820, Email k432@sakura.medtoho-u.ac.jpAbstract: Obesity-induced heart failure (HF) in young people is a serious problem. The treatments for HF have developed in recent years. The following four basic HF drugs have been widely recognized as the “Fantastic Four”: beta-adrenergic blocking agents, mineralocorticoid receptor antagonists (MRA), sodium glucose transporter 2 inhibitors (SGLT2 inhibitors), and angiotensin receptor neprilysin inhibitors (ARNI). However, the interaction between the heart and blood vessels has not received much attention. The cardio-ankle vascular index (CAVI) is an arterial stiffness index that is unaffected by blood pressure at the time of measurement. A 34-year-old obese man was admitted with dyspnea and edema. His cardiac function was severely impaired, and CAVI was increased. After administration of multidisciplinary HF treatment centered on the “Fantastic Four”, his cardiac function and CAVI improved dramatically in a short time period. This case suggests the importance of improvement both cardiac and vascular function for the treatment of HF.Keywords: obesity, hypertension, obstructive sleep apnea, arterial stiffness, cardio ankle vascular index

Kazuhiro Shimizu,1 Mao Takahashi,1 Shuji Sato,1 Atsuhito Saiki,1 Daiji Nagayama,1,2 Takashi Hitsumoto,3 Akira Takahara,4 Kohji Shirai1,5 1Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, Japan; 2Department of Internal Medicine, Nagayama Clinic, Oyama, Tochigi, Japan; 3Hitsumoto Medical Clinic, Shimonoseki, Yamaguchi, Japan; 4Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, Japan; 5Department of Internal Medicine, Seijinkai Mihama Hospital, Chiba, Chiba, JapanCorrespondence: Kazuhiro Shimizu, Department of Internal Medicine, Toho University Sakura Medical Center, 561-4 Shimoshizu, Sakura, Chiba, 285-8741, Japan, Tel +81-43-462-8811, Fax +81-43-462-8820, Email k432@sakura.med.toho-u.ac.jpAbstract: Predictive factors for vascular events have not been established. The vasculature of the atheroma is supplied by penetration of the vasa vasorum through the smooth muscle cell layer from the adventitia. Smooth muscle cell contraction induces compression of the vasa vasorum, resulting in ischemia in intimal atheromatous lesions. Cardio-ankle vascular index (CAVI) has become known as an index of arterial stiffness of the arterial tree from the origin of the aorta to the ankle. CAVI reflects the progress of arteriosclerosis, and a rapid rise in CAVI indicates arterial smooth muscle cell contraction. We hypothesized that rapidly increased arterial stiffness evaluated by CAVI may be a predictor of impending cardiovascular events.Keywords: arterial stiffness, stress, plaque rupture, CAVI

BACKGROUND: Arterial stiffness is an important predictor of cardiovascular events; however, indexes for measuring arterial stiffness have not been widely incorporated into routine clinical practice. This study aimed to determine whether the cardio-ankle vascular index (CAVI), based on the blood pressure-independent stiffness parameter beta and reflecting arterial stiffness from the origin of the ascending aorta, is a good predictor of cardiovascular events in patients with cardiovascular disease risk factors in a large prospective cohort. METHODS AND RESULTS: This multicenter prospective cohort study, commencing in May 2013, with a 5-year follow-up period, included patients (aged 40-74 years) with cardiovascular disease risks. The primary outcome was the composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Among 2932 included patients, 2001 (68.3%) were men; the mean (SD) age at diagnosis was 63 (8) years. During the median follow-up of 4.9 years, 82 participants experienced primary outcomes. The CAVI predicted the primary outcome (hazard ratio, 1.38; 95% CI, 1.16-1.65; P<0.001). In terms of event subtypes, the CAVI was associated with cardiovascular death and stroke but not with myocardial infarction. When the CAVI was incorporated into a model with known cardiovascular disease risks for predicting cardiovascular events, the global chi(2) value increased from 33.8 to 45.2 (P<0.001), and the net reclassification index was 0.254 (P=0.024). CONCLUSIONS: This large cohort study demonstrated that the CAVI predicted cardiovascular events.

Kazuhiro Shimizu,1 Mao Takahashi,1 Shuji Sato,1 Atsuhito Saiki,1 Daiji Nagayama,1 Masashi Harada,2 Chikao Miyazaki,2 Akira Takahara,3 Kohji Shirai1 1Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, Japan; 2Department of Neurosurgery, Toho University Omori Medical Center, Omori, Tokyo, Japan; 3Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, JapanCorrespondence: Kohji ShiraiDepartment of Internal Medicine, Toho University Sakura Medical Center, 561-4 Shimoshizu, Sakura City, Chiba, 285-8741, JapanTel +81-43-462-8811Fax +81-43-462-8820Email kshirai@kb3.so-net.ne.jpAbstract: Cardiovascular diseases have been recognized as the main cause of death all over the world. Recently, the established cardio-ankle vascular index (CAVI) has become known as an index of arterial stiffness of the arterial tree from the origin of the aorta to the ankle. CAVI reflects the progress of arteriosclerosis, and a rapid rise in CAVI indicates arterial smooth muscle cell contraction. Considering the vasculature of the atheroma where vasa vasorum penetrates the smooth muscle cell layer and supplies blood to the intimal atheromatous lesion, a rapid rise of CAVI means “choked” atheroma. Thus, we proposed a “smooth muscle cell contraction” hypothesis of plaque rupture.Keywords: arterial stiffness, atherosclerosis, smooth muscle cell contraction, CAVI