Night-Time Hot Spring Bathing Is Associated with a Lower Systolic Blood Pressure among Japanese Older Adults: A Single-Institution Retrospective Cohort Study.

Hot spring bathing is practiced to help manage hypertension. We retrospectively investigated the effects of hot spring bathing on hypertension with the aim of identifying a novel approach to prevent and manage hypertension. The study cohort comprised 99 patients aged ≥65 years admitted to Kyushu University Beppu Hospital between 1 December 2021 and 30 November 2022 who could walk by themselves and who used hot springs for ≥3 days during their hospital stay. The changes in both systolic and diastolic blood pressure were significantly decreased in the night-time bathing group (n = 21) compared with the noontime (n = 26) and afternoon (n = 52) groups. Night-time hot spring bathing was significantly associated with reduced systolic blood pressure the next morning in older adults. Although prospective randomized controlled trials on night-time hot spring bathing as a hypertension treatment are warranted to investigate whether the practice can prevent hypertension among adults aged ≥65 years, we have initiated a single-center, phase II study on the relationship between sleep quality and quality of life in hypertensive patients after night-time hot spring bathing.

Hot spring bathing is associated with a lower prevalence of hypertension among Japanese older adults: a cross-sectional study in Beppu.

Hot spring bathing is practiced to help manage various diseases, including hypertension. We investigated the preventive effects on hypertension of hot spring bathing among older adults in a data analysis using responses to a previous questionnaire with the aim to identify a novel approach in the prevention and management of hypertension. Among 10,428 adults aged ≥ 65 years, we assessed the hot spring bathing habits of 4001 individuals with a history of hypertension. We calculated odds ratios (OR) with 95% confidence intervals using a multivariable logistic regression model for history of hypertension. In multivariable logistic regression, age (≥ 85 years: OR, 1.410); history of arrythmia (OR, 1.580), stroke (OR, 1.590), gout (OR, 1.880), diabetes mellitus (OR, 1.470), hyperlipidemia (OR, 1.680), renal disease (OR, 1.520), chronic hepatitis (OR, 0.648); and hot spring bathing at 19:00 or later (OR, 0.850) were independently and significantly associated with hypertension during the lifetime. We found an inverse relationship between habitual nighttime hot spring bathing and a history of depression. Prospective randomized controlled trials on nighttime hot spring bathing as a treatment for hypertension are warranted to investigate whether nighttime hot spring bathing can help in preventing hypertension among adults aged ≥ 65 years.

Factors Associated with Discontinuation of Statin Therapy in Patients with Lymphoma Aged 80 Years and Older: A Retrospective Single-Institute Study.

BACKGROUND: There is little evidence to support or negate the benefits of statin therapy for primary prevention of cardiovascular disease (CVD) in lymphoma patients aged 80 years or older. OBJECTIVE: We evaluated comprehensive geriatric assessment (CGA) scores and previously reported risk factors for failure of statin therapy discontinuation in lymphoma patients aged 80 years and older with the aim of identifying those in whom discontinuation of statins for primary CVD prevention is indicated. PATIENTS AND METHODS: Our study cohort comprised 50 patients aged 80 years and older treated with chemotherapy for lymphoma at our institute from January 2011 to July 2020. We retrospectively analyzed the associations between CGA, including Geriatric 8, instrumental activities of daily living, and Charlson comorbidity index, and previously reported factors associated with failure of statin therapy discontinuation, defined as reintroduction of statins after their discontinuation, in this patient cohort. RESULTS: Twenty years or less of statin therapy was an independent predictor of failure of statin therapy discontinuation (hazard ratio 8.240, 95% confidence interval 1.380-49.10). There were significant differences in the rate of failure of statin discontinuation between patients receiving statins for ≥ 20 years versus < 20 years (p = 0.010). Multivariate analysis of CGA-related scores identified no significant risk factors for failure of statin discontinuation. CONCLUSIONS: Discontinuation of statin therapy may be indicated in lymphoma patients aged 80 years and older who have used statins for 20 years or more.

Recent advances in the management of secondary hypertension-obstructive sleep apnea.

Since obstructive sleep apnea (OSA) is known as a common cause of secondary hypertension, it is necessary to consider OSA a differential diagnosis in treating patients with hypertension. Apnea during sleep causes temporary and repeated hypoxia and subsequent sympathetic nerve activation. Furthermore, dysfunction of endothelial cells due to hypoxia is considered another mechanism leading to enhanced stiffness of the elastic artery and eventually, elevation of blood pressure (BP). As a result, OSA induces a nighttime or morning surge in BP, and long-standing severe OSA also causes daytime hypertension. Therefore, treatment of OSA may be important for BP control, especially in severe OSA cases. For the treatment of OSA, continuous positive airway pressure (CPAP) is a major treatment option, though alternative devices may be useful in CPAP-intolerant cases.

Accumulated nocturnal hypoxemia predict arterial endothelial function in patients with sleep-disordered breathing with or without chronic heart failure.

ABTSRACT: Sleep-disordered breathing (SDB) is often accompanied with the chronic heart failure (CHF). Hypoxemia due to pulmonary congestion from CHF and concurrent SDB might synergistically impair endothelial function and worsen the prognosis. However, the main factors affecting deterioration of endothelial function are unknown and whether the influence of hypoxemia differs in SDB patients with and without CHF remains unclear. Fifty-three patients (CHF group, n = 23; non-CHF group, n = 30) underwent polysomnography to evaluate their SDB and flow-mediated vasodilation (FMD) measurements to assess arterial endothelial function. We examined the relationships between FMD and SDB-related parameters, including our original index of accumulated hypoxemia by SDB throughout one-night sleep: the time desaturation summation index (TDS), calculated as follows: (100% - averaged arterial oxygen saturation during sleep) × total sleep time. The mean age in the CHF and non-CHF groups was 59.0 ± 13.5 and 57.7 ± 11.4 years, respectively. Although the FMD in the 2 groups were not significantly different, well-known adverse factors for FMD such as serum lipid profiles, blood pressure levels, and conventional indices of SDB were worse in the non-CHF group. Only the TDS was not significantly different between 2 groups and associated with FMD as shown by the univariate analysis (CHF: p < 0.05, non-CHF: p < 0.01) and multivariate analysis (CHF: p < 0.05, non-CHF: p < 0.01). Accumulated hypoxemia (TDS) rather than the frequency of hypoxemia might more influence on the endothelial function irrespective of the cardiac state. Removal of accumulation of nocturnal hypoxemia might be a target for treatment equally in the patients with and without CHF.

Hypoxia-inducible factor-1 α deletion in myeloid lineage attenuates hypoxia-induced pulmonary hypertension.

Hypoxemia is seen in patients with pulmonary hypertension and hypoxic pulmonary vasoconstriction worsens their clinical condition. However, vasoconstriction is not the only aspect through which hypoxia induces the progression to pulmonary hypertension. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor responding to hypoxic conditions by regulating hundreds of genes involved in angiogenesis, erythropoiesis, inflammation, and proliferation. We sought to determine the contribution of HIF-1α in myeloid lineage cells to the pulmonary vascular response to chronic exposure to hypoxia. We generated myeloid-specific HIF-1α knockout (MyeHIF1KO) mice by using Cre-lox P system, and exposed them to hypoxic conditions for 3 weeks to induce pulmonary hypertension. Macrophages from MyeHIF1KO and control mice were used for western blotting, RT-qPCR, chemotaxis assay, and ATP assay. MyeHIF1KO mice exposed to hypoxia for 3 weeks exhibited a significant reduction in the right ventricular systolic pressure accompanied by a decrease in the ratio of the right ventricular weight to left ventricular weight, muscularization of the small pulmonary arteries, and infiltration of macrophages into the lung and right ventricle compared with control mice. HIF-1α-deficient peritoneal macrophages showed less migration toward monocyte chemoattractant protein-1 and a decrease in intracellular ATP levels. These results indicate that HIF-1α in macrophages contributes to the progression of pulmonary vascular remodeling and pulmonary hypertension induced by chronic exposure to hypoxic conditions. The inhibition of myeloid-specific HIF-1α may be a novel therapeutic strategy for the treatment of pulmonary hypertension.

Accumulation of gold nano-rods in the failing heart of transgenic mice with the cardiac-specific expression of TNF-α.

Gold nano-rods, rod-shaped gold nanoparticles, act as contrast agents for in vivo bioimaging, drug delivery vehicles and thermal converters for photothermal therapy. Pro-inflammatory cytokines play critical roles in the development of heart failure. We examined the delivery of GNRs into the failing heart of a transgenic (TG) mouse model of inflammatory cardiomyopathy with the cardiac-specific overexpression of TNF-α. We modified GNRs with polyethylene glycol (PEG) to avoid cytotoxicity and reduce the rapid clearance of nanoparticles from blood. PEG-modified GNRs (4.5 mM as gold atoms, 200 µL) were administered intravenously to TG (n = 7) and wild-type (WT) mice (n = 5). These were killed 24 h later, and the heart, lung, liver, kidney and spleen were excised. A quantitative analysis of gold was performed using inductively coupled plasma mass or optical emission spectrometry. The amount of gold (ng) in the TG heart (3.24 ± 1.56 ng/mg heart weight) was significantly greater than that in the WT heart (1.01 ± 0.19; p < 0.05). No significant differences were observed among the other organs of TG and WT mice. The amount of gold in the TG heart was significantly and positively correlated with the ratio of the ventricular weight to body weight, which is known to be an index of ventricular hypertrophy. In conclusion, PEG-modified GNRs accumulated in the inflammatory TG heart in proportion with the severity of ventricular hypertrophy.

Suppression of Abdominal Aortic Aneurysm Formation in Mice by Teneligliptin, a Dipeptidyl Peptidase-4 Inhibitor.

AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels through inhibition of incretin degradation, which stimulates insulin secretion. Recent studies reported that DPP-4 inhibitors suppressed atherogenesis in apolipoprotein E-knockout (ApoEKO) mice. In this study, we investigated whether teneligliptin, a DPP-4 inhibitor, affects the development of abdominal aortic aneurysms (AAA) in ApoEKO mice. METHODS: ApoEKO mice were fed a high-fat diet (HFD) and infused with angiotensin (Ang) II by osmotic mini pumps for 4 weeks to induce AAA with (DPP-4i group) or without (control group) teneligliptin administered orally from 1 week before HFD and Ang II infusion to the end of the experiment. Confluent rat vascular smooth muscle cells (VSMCs) were serum-starved for 48 hours, then incubated with or without teneligliptin for another 24 hours and stimulated with Ang II. RESULTS: Treatment with teneligliptin significantly reduced the AAA formation rate (30.7% vs. 71.4% vs. control, P＜0.05), aortic dilatation (1.32±0.09 mm vs. 1.76±0.18 mm in the control, P＜0.05) and severity score (0.75±0.28 vs. 1.91±0.4 in the control, P＜0.05). Elastin degradation grade was also attenuated in DPP-4i group (2.83±0.17 vs. 3.45±0.16 in the control, P＜0.05). The number of macrophages infiltrating into the abdominal aorta was decreased in the DPP-4i group (51.8± 29.8/section vs. 219.5±78.5/section in the control, P＜0.05). Teneligliptin attenuated Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and mRNA expression of monocyte chemoattractant protein-1 in VSMCs. CONCLUSION: Treatment with teneligliptin suppressed AAA formation in ApoEKO mice with HFD and Ang II infusion. Suppression of macrophage infiltration by teneligliptin may be involved in the inhibition of AAA formation.

Cardiac Sarcoidosis Concomitant with Large-vessel Aortitis Detected by 18F-fluorodeoxyglucose Positron Emission Tomography.

We herein report a case of concurrent cardiac sarcoidosis and large-vessel aortitis detected by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and followed up during immunosuppressive therapy. After high-dose prednisolone administration (1 mg/kg), serial FDG-PET showed that almost all of the abnormal FDG uptake in the heart and extracardiac region, including the abdominal to bilateral iliac arteries, had been disappeared. During the tapering of prednisolone, additive methotrexate therapy was needed to treat the recurrence of cardiac sarcoidosis. FDG-PET is a useful tool for detecting cardiac sarcoidosis concomitant with large-vessel aortitis and monitoring the effectiveness of immunosuppressive therapy.

Deletion of hypoxia-inducible factor-1α in myeloid lineage exaggerates angiotensin II-induced formation of abdominal aortic aneurysm.

Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates various genes responding to hypoxic conditions. We previously reported that myeloid-specific activation of HIF-1α had protective effects on hypertensive cardiovascular remodelling in mice. However the role of myeloid lineage HIF-1α in the development of abdominal aortic aneurysm (AAA) has not been determined. Myeloid-specific HIF-1α knockout (HIF-1KO) mice were created using a Cre-lox recombination system in the background of apolipoprotein E-deficient (ApoE-/-) mice. HIF-1KO and control mice were fed high-fat diet (HFD) and infused with angiotensin II (Ang II, 1800 ng/kg/min) by an osmotic mini pump for 4 weeks to induce AAA formation. Deletion of HIF-1α increased aortic external diameter (2.47±0.21 mm versus 1.80±0.28 mm in control, P=0.035). AAA formation rate (94.4% in HIF-1KO versus 81.8% in control) was not statistically significant. Elastic lamina degradation grade determined by Elastica van Gieson (EVG) staining was deteriorated in HIF-1KO mice (3.91±0.08 versus 3.25±0.31 in control, P=0.013). The number of infiltrated macrophages into the abdominal aorta was increased in HIF-1KO mice. Expression of tissue inhibitors of metalloproteinases (TIMPs) was suppressed in the aorta and peritoneal macrophages (PMs) from HIF-1KO mice compared with control mice. HIF-1α in myeloid lineage cells may have a protective role against AAA formation induced by Ang II and HFD in ApoE-/- mice.

Cumulative Hypoxemia During Sleep Predicts Vascular Endothelial Dysfunction in Patients With Sleep-Disordered Breathing.

BACKGROUND: Sleep-disordered breathing (SDB) is associated with repeated intermittent hypoxemia, and it is known as one of the risk factors for cardiovascular diseases. Previous studies assessing the effects of frequency and depth of hypoxemia on cardiovascular diseases have shown conflicting results. The aim of the current study was to clarify what SDB-related parameters most predict endothelial dysfunction to better understand the pathogenesis of endothelial dysfunction in patients with SDB. METHODS: We conducted polysomnography (PSG) and measured flow-mediated vasodilation response (%FMD) in 50 outpatients suspected of SDB. Evaluated indices included: apnea-hypopnea index (AHI), 3% oxygen desaturation index (3%ODI), averaged arterial oxygen saturation (averaged SpO2), lowest arterial oxygen saturation (lowest SpO2), ratio of arterial oxygen saturation <90% (

Suppression of abdominal aortic aneurysm formation by AR-R17779, an agonist for the α7 nicotinic acetylcholine receptor.

OBJECTIVE: Activation of vagal nerve suppresses inflammatory responses through activation of α7 nicotinic acetylcholine receptor (nAchR). We sought to determine whether AR-R17779, a selective agonist of α7nAchR, affects the development of abdominal aortic aneurysm (AAA). METHODS AND RESULTS: AAA was induced by topical application of calcium chloride (CaCl2) to abdominal aorta (AAA group). NaCl (0.9%) was substituted for CaCl2 as a sham operation (SHAM group). AR-R17779 was administered in drinking water (AAA/AR-R group). One and 6 weeks after the operation, aortic tissue was excised for histological and molecular analyses. Aortic diameter and macrophage infiltration into the aortic adventitia were increased in AAA group compared with SHAM group at 6 weeks. Treatment with AR-R17779 reduced the diameter of the aorta and macrophage infiltration compared with AAA group. Wavy morphology of the elastic lamellae was lost in AAA group while it was preserved in AAA/AR-R group. Expression of inflammatory cytokines and matrix metalloproteinase (MMP) activities were enhanced in AAA group, which was suppressed in AAA/AR-R group. AR-R17779 treatment suppressed CaCl2-induced expression of cytokines, activities of MMPs and NF-κB activation at 1 week when aortic dilatation had not developed. CONCLUSION: Treatment with AR-R17779 prevented the enlargement of abdominal aorta induced by CaCl2 in association with reduced inflammation and extracellular matrix disruption. These findings suggest therapeutic potential of α7nAchR activation for prevention of AAA development.

PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages.

BACKGROUND: Clinical trials have shown that treatment of patients with type 2 diabetes with pioglitazone, a peroxisome proliferator-activated receptor (PPAR)γ agonist, reduces cardiovascular events. However, the effect of PPARγ agonists on endoplasmic reticulum (ER) stress that plays an important role in the progression of atherosclerosis has not been determined. We sought to determine the effect of PPARγ agonists on ER stress induced by palmitate, the most abundant saturated fatty acid in the serum. METHODS AND RESULTS: Protein expression of ER stress marker was evaluated by Western blot analysis and stearoyl-CoA desaturase1 (SCD-1) mRNA expression was evaluated by qRT-PCR. Macrophage apoptosis was detected by flowcytometry. Pioglitazone and rosiglitazone reduced palmitate-induced phosphorylation of PERK, a marker of ER stress, in RAW264.7, a murine macrophage cell line. Pioglitazone also suppressed palmitate-induced apoptosis in association with inhibition of CHOP expression, JNK phosphorylation and cleavage of caspase-3. These effects of pioglitazone were reversed by GW9662, a PPARγ antagonist, indicating that PPARγ is involved in this process. PPARγ agonists increased expression of SCD-1 that introduces a double bond on the acyl chain of long-chain fatty acid. 4-(2-Chlorophenoxy)-N-(3-(3-methylcarbamoyl)phenyl)piperidine-1-carboxamide, an inhibitor of SCD-1, abolished the anti-ER stress and anti-apoptotic effects of pioglitazone. These results suggest that PPARγ agonists attenuate palmitate-induced ER stress and apoptosis through SCD-1 induction. Up-regulation of SCD-1 may contribute to the reduction of cardiovascular events by treatment with PPARγ agonists.

Stimulation of α7 nicotinic acetylcholine receptor by AR-R17779 suppresses atherosclerosis and aortic aneurysm formation in apolipoprotein E-deficient mice.

Atherosclerosis is a chronic inflammatory disease. It has been appreciated that vagus nerve inhibits macrophage activation via α7 nicotinic acetylcholine receptor (nAChR), termed the cholinergic anti-inflammatory pathway. We explored the effects of AR-R17779, a selective α7nAChR agonist, on atherosclerosis and aneurysm formation in apolipoprotein E (ApoE)-deficient mice. ApoE-deficient mice were fed a high-fat diet (HFD) and angiotensin II (Ang II) was infused by osmotic minipumps from 10-week-old for 4weeks. AR-R17779 was given in drinking water ad libitum. Oil red O staining of the aorta showed that combined loading of HFD and Ang II induced marked atherosclerosis compared with control mice fed a normal chow. Treatment with AR-R17779 significantly reduced atherosclerotic plaque area and improved survival of mice. Treatment with AR-R17779 also suppressed abdominal aortic aneurysm formation. Quantitative RT-PCR of the aorta revealed that mRNA expression levels of interleukin-1ß, interleukin-6 and NOX2 were significantly decreased in AR-R17779-treated mice compared with Ang II+HFD mice. AR-R17779 treatment also reduced blood pressure and serum lipid levels. In conclusion, α7nAChR activation attenuates atherogenesis and aortic abdominal aneurysm formation in ApoE-deficient mice possibly through an anti-inflammatory effect and reduction of blood pressure and lipid levels. Pharmacological activation of α7nAChR may have a therapeutic potential against atherosclerotic vascular diseases through multiple mechanisms.

Suppression of abdominal aortic aneurysm formation by inhibition of prolyl hydroxylase domain protein through attenuation of inflammation and extracellular matrix disruption.

In the present study we sought to determine the effect of CoCl2, an inhibitor of PHD (prolyl hydroxylase domain protein), on the development of AAA (abdominal aortic aneurysm). AAA was induced in C57BL/6 mice by periaortic application of CaCl2 (AAA group). NaCl (0.9%)-treated mice were used as a sham control (SHAM group). Mice were treated with 0.05% CoCl2 in the drinking water (AAA/CoCl2 group). At 1 and 6 weeks after the operation, aortic tissue was excised for further examination. After 6 weeks of CaCl2 treatment, aortic diameter and macrophage infiltration into the aortic adventitia were increased in the AAA group compared with the SHAM group. Treatment with CoCl2 reduced the aneurysmal size and macrophage infiltration compared with the AAA group. Aortic expression of inflammatory cytokines and MCP-1 (monocyte chemoattractant protein-1) and the activities of MMP-9 (matrix metalloproteinase-9) and MMP-2 were enhanced in the AAA group and attenuated in the AAA/CoCl2 group. Expression of cytokines and the activities of MMPs were already increased after 1 week of CaCl2 treatment, but were suppressed by CoCl2 treatment in association with reduced NF-κB (nuclear factor κB) phosphorylation. Treatment with CoCl2 in mice prevented the development of CaCl2-induced AAA in association with reduced inflammation and ECM (extracellular matrix) disruption. The results of the present study suggest that PHD plays a critical role in the development of AAA and that there is a therapeutic potential for PHD inhibitors in the prevention of AAA development.

Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling.

BACKGROUND: Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates the proline residues of hypoxia-inducible factor-α (HIF-α) and thereby induces HIF-α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid-specific Phd2 deletion affects hypertension-induced cardiovascular remodeling. METHODS AND RESULTS: Myeloid-specific PHD2-deficient mice (MyPHD2KO) were generated by crossing Phd2-floxed mice with LysM-Cre transgenic mice, resulting in the accumulation of HIF-1α and HIF-2α in macrophage. Eight- to ten-week-old mice were given N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L-NAME/Ang II comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial and adventitial thickening, and macrophage infiltration. Cardiac interstitial fibrosis and myocyte hypertrophy were also significantly ameliorated in MyPHD2KO mice. Transforming growth factor-ß and collagen expression were decreased in the aorta and heart from MyPHD2KO mice. Echocardiographic analysis showed that left ventricular hypertrophy and reduced ejection fraction induced by L-NAME/Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits HIF-α synthesis to L-NAME/Ang II-treated MyPHD2KO mice reversed these beneficial features. CONCLUSIONS: Phd2 deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation- and fibrosis-associated gene expression in macrophages. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling.

Resveratrol attenuates angiotensin II-induced senescence of vascular smooth muscle cells.

Resveratrol (3,5,4'-trihydroxystilbene), a polyphenol abundant in red wine, is known to extend the life span of diverse species. On the contrary, it was reported that angiotensin (Ang) II enhances senescence of vascular smooth muscle cells (VSMCs). We, therefore, examined whether resveratrol attenuates Ang II-induced senescence of VSMC. Senescence-associated ß-galactosidase (SA ß-gal) assay showed that Ang II induced senescence of VSMC. The Ang II-induced senescence was inhibited by losartan, an Ang II type 1 receptor (AT1R) antagonist but not by PD123319, Ang II type 2 receptor antagonist, indicating that AT1R is responsible for the induction of senescence. Resveratrol suppressed Ang II-induced senescence of VSMC in a dose-dependent manner. In addition, resveratrol suppressed Ang II-induced induction of p53 and its downstream target gene p21, both of which play an important role in the induction of senescence. Resveratrol suppressed senescence of VSMC possibly through inhibition of AT1R-dependent induction of p53/p21. Suppression of p53 induction may be involved in the longevity by resveratrol.

Recurrence of Takotsubo cardiomyopathy with coronary slow flow phenomenon.

This report presents the case of a 54-year-old female with Takotsubo cardiomyopathy that recurred 12 years after the first episode. The coronary angiography at the first admission revealed ergonovine-induced coronary vasoconstriction in the left coronary artery, and recurrence recurred after the interruption of vasodilator therapy to prevent vasospasm. In addition, the coronary angiography both in the first and second event demonstrated coronary slow flow phenomenon, which improved after the intracoronary administration of nicorandil. These findings indicate that coronary microvascular constriction plays an important role in the pathophysiology of Takotsubo cardiomyopathy.

Inhibition of prolyl hydroxylase domain-containing protein downregulates vascular angiotensin II type 1 receptor.

Inhibition of prolyl hydroxylase domain-containing protein (PHD) by hypoxia stabilizes hypoxia-inducible factor 1 and increases the expression of target genes, such as vascular endothelial growth factor. Although the systemic renin-angiotensin system is activated by hypoxia, the role of PHD in the regulation of the renin-angiotensin system remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin II type 1 receptor (AT(1)R). Hypoxia, cobalt chloride, and dimethyloxalylglycine, all known to inhibit PHD, reduced AT(1)R expression in vascular smooth muscle cells. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT(1)R expression. Cobalt chloride diminished angiotensin II-induced extracellular signal-regulated kinase phosphorylation. Cobalt chloride decreased AT(1)R mRNA through transcriptional and posttranscriptional mechanisms. Oral administration of cobalt chloride (14 mg/kg per day) to C57BL/6J mice receiving angiotensin II infusion (490 ng/kg per minute) for 4 weeks significantly attenuated perivascular fibrosis of the coronary arteries without affecting blood pressure level. These data suggest that PHD inhibition may be beneficial for the treatment of cardiovascular diseases by inhibiting renin-angiotensin system via AT(1)R downregulation.