Cigarette Smoking and Atherosclerotic Cardiovascular Disease.

The detrimental effects of cigarette smoking on cardiovascular health, particularly atherosclerosis and thrombosis, are well established, and more detailed mechanisms continue to emerge. As the fundamental pathophysiology of the adverse effects of smoking, endothelial dysfunction, inflammation, and thrombosis are considered to be particularly important. Cigarette smoke induces endothelial dysfunction, leading to impaired vascular dilation and hemostasis regulation. Factors contributing to endothelial dysfunction include reduced bioavailability of nitric oxide, increased levels of superoxide anion, and endothelin release. Chronic inflammation of the vascular wall is a central pathogenesis of smoking-induced atherosclerosis. Smoking systemically elevates inflammatory markers and induces the expression of adhesion molecules and cytokines in various tissues. Pattern recognition receptors and damage-associated molecular patterns play crucial roles in the mechanism underlying smoking-induced inflammation. Smoking-induced DNA damage and activation of innate immunity, such as the NLRP3 inflammasome, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, and Toll-like receptor 9, are shown to amplify inflammatory cytokine expression. Cigarette smoke-induced oxidative stress and inflammation influence platelet adhesion, aggregation, and coagulation via adhesion molecule upregulation. Furthermore, it affects the coagulation cascade and fibrinolysis balance, causing thrombus formation. Matrix metalloproteinases contribute to plaque vulnerability and atherothrombotic events. The impact of smoking on inflammatory cells and adhesion molecules further intensifies the risk of atherothrombosis. Collectively, exposure to cigarette smoke exerts profound effects on endothelial function, inflammation, and thrombosis, contributing to the development and progression of atherosclerosis and atherothrombotic cardiovascular diseases. Understanding these intricate mechanisms highlights the urgent need for smoking cessation to protect cardiovascular health. This comprehensive review investigates the multifaceted mechanisms through which smoking contributes to these life-threatening conditions.

Mitochondrial DNA is a key driver in cigarette smoke extract-induced IL-6 expression.

Smoking is an independent risk factor for atherosclerosis, the primary pathogenesis of which is inflammation. We recently reported that cigarette smoke extract (CSE) causes cytosolic and extracellular accumulation of both nuclear (n) and mitochondrial (mt) DNA, which leads to inflammation in human umbilical vein endothelial cells (HUVECs). In this study, we examined whether inflammation induction depends more on cytosolic nDNA or mtDNA, and which chemical constituents of CSE are involved. Acrolein (ACR), methyl vinyl ketone (MVK), and 2-cyclopenten-1-one (CPO) were used in the experiments, as these are the major cytotoxic factors in CSE in various cell types. Stimulation with ACR, MVK, or CPO alone resulted in the accumulation of DNA double-strand breaks (DSBs), but not oxidative DNA damage, accumulation of cytosolic DNA, or increased expression of inflammatory cytokines. Simultaneous administration of all three constituents (ALL) resulted in oxidative DNA damage in both the nucleus and mitochondria, accumulation of DSBs, reduced mitochondrial membrane potential, induction of minority mitochondrial outer membrane permeabilization, accumulation of cytosolic free DNA, and increased expression of inflammatory cytokines such as IL-6 and IL-1α. Treatment with N-acetyl-L-cysteine, a reactive oxygen species scavenger, suppressed oxidative DNA damage and the increased expression of IL-6 and IL-1α induced by ALL or CSE. The ALL- or CSE-induced increase in IL-6 expression, but not that of IL-1α, was suppressed by mtDNA depletion. In conclusion, ACR, MVK, and CPO may strongly contribute to CSE-induced inflammation. More importantly, cytosolic free mtDNA is thought to play an important role in IL-6 expression, a central mediator of inflammation.

Cardiovascular Hospitalizations and Hospitalization Costs in Japan During the COVID-19 Pandemic.

Background: During the COVID-19 pandemic, cardiovascular hospitalizations decreased and in-hospital mortality for ST-elevation myocardial infarction and heart failure increased. However, limited research has been conducted on hospitalization and mortality rates for cardiovascular disease (CVD) other than ischemic heart disease and heart failure. Methods and Results: We analyzed the records of 530 certified hospitals affiliated with the Japanese Circulation Society obtained from the nationwide JROAD-DPC database between April 2014 and March 2021. A quasi-Poisson regression model was used to predict the counterfactual number of hospitalizations for CVD treatment, assuming there was no pandemic. The observed number of inpatients compared with the predicted number in 2020 was 88.1% for acute CVD, 78% for surgeries or procedures, 77.2% for catheter ablation, and 68.5% for left ventricular assist devices. Furthermore, there was no significant change in in-hospital mortality, and the decrease in hospitalizations for catheter ablation and valvular heart disease constituted 47.6% of the total decrease in annual hospitalization costs during the COVID-19 pandemic. Conclusions: Cardiovascular hospitalizations decreased by more than 10% in 2020, and the number of patients scheduled for left ventricular assist device implantation decreased by over 30%. In addition, in response to the COVID-19 pandemic, annual cardiovascular hospitalization costs were reduced, largely attributed to decreased catheter ablation and valvular heart disease.

A possible role for proinflammatory activation via cGAS-STING pathway in atherosclerosis induced by accumulation of DNA double-strand breaks.

DNA damage contributes to atherosclerosis. However, causative links between DNA double-strand breaks (DSBs) and atherosclerosis have yet to be established. Here, we investigated the role of DSBs in atherosclerosis using mice and vascular cells deficient in Ku80, a DSB repair protein. After 4 weeks of a high-fat diet, Ku80-deficient apolipoprotein E knockout mice (Ku80+/-ApoE-/-) displayed increased plaque size and DSBs in the aorta compared to those of ApoE-/- control. In the preatherosclerotic stages (two-week high-fat diet), the plaque size was similar in both the Ku80+/-ApoE-/- and ApoE-/- control mice, but the number of DSBs and mRNA levels of inflammatory cytokines such as IL-6 and MCP-1 were significantly increased in the Ku80+/-ApoE-/- aortas. We further investigated molecular links between DSBs and inflammatory responses using vascular smooth muscle cells isolated from Ku80 wild-type and Ku80+/- mice. The Ku80+/- cells displayed senescent features and elevated levels of inflammatory cytokine mRNAs. Moreover, the cytosolic DNA-sensing cGAS-STING pathway was activated in the Ku80+/- cells. Inhibiting the cGAS-STING pathway reduced IL-6 mRNA level. Notably, interferon regulatory factor 3 (IRF3), a downstream effector of the cGAS-STING pathway, was activated, and the depletion of IRF3 also reduced IL-6 mRNA levels in the Ku80+/- cells. Finally, DSBs accumulation in normal cells also activated the cGAS-STING-IRF3 pathway. In addition, cGAS inhibition attenuated DNA damage-induced IL-6 expression and cellular senescence in these cells. These results suggest that DSBs accumulation promoted atherosclerosis by upregulating proinflammatory responses and cellular senescence via the cGAS-STING (-IRF3) pathway.

Impact of Tweet Content on the Number of Retweets　- "Tweet the Meeting 2022".

Background: Previous research has investigated the effectiveness of the "Tweet the Meeting" campaign, but the relationship between tweet content and the number of retweets has not been fully evaluated. Methods and Results: We analyzed the number of tweets and retweets during the Japanese Circulation Society's 2022 annual meeting. The ambassador group had significantly more session- and symposium-related tweets than the non-ambassador group (P<0.001), associated with the nubmer of retweets. Symposium-related tweets with figures generated more retweets than those without figures (mean [±SD] 3.47±3.31 vs. 2.48±1.94 retweets per tweet, respectively; P=0.001). Conclusions: The study revealed that official meeting-designated Twitter ambassadors disseminate more educational content than non-ambassadors, and generated more retweets.

Factors Influencing Acceptance of the Chairperson Position at Annual Scientific Meetings of the Japanese Circulation Society　- A Questionnaire Survey in Chugoku District.

Background: The Japanese Circulation Society survey revealed that Japanese female cardiologists exhibited a trend to refuse the chairperson position; however, the causal factors remain uncertain. Methods and Results: We distributed a questionnaire survey among chairpersons of the Chugoku regional meeting in November 2022. The rate of chair acceptance at the annual meeting tended to increase as the chairperson's experience grew (first time chairing a meeting, 25.0%; 2-3 times, 33.3%; 4-5 times, 53.8%; ≥6 times, 70.0%; P=0.021). Conclusions: Providing inexperienced members with the chance to perform the role of chairperson will lead to them accepting to chair annual meetings.

The time trend of information seeking behavior about salt reduction using Google Trends: infodemiological study in Japan.

Numerous initiatives have been implemented to reduce salt intake to prevent hypertension and cardiovascular disease. However, salt consumption remains high. No study worldwide has evaluated the public's awareness of salt reduction by analyzing Internet research activity. This research aims to assess trends in the public's attention to salt reduction using Google Trends. We evaluated the relative search volume (RSV) of "salt reduction" in Google Trends from January 1, 2004, to December 31, 2021. Regression coefficients indicated that RSVs increased 0.0091 (95% CI, 0.0085-0.0097, p < 0.001) per year for salt reduction. Among related search terms, search for "salt component," "soy sauce," and "pickled plum" contributed to 9.9 ± 3.2%, 5.8 ± 2.0%, and 3.9 ± 5.5% of total RSVs for salt reduction. Google Trends revealed that the Japanese public's awareness of salt reduction has increased. Related searches might provide insights when people search for salt reduction, which could be helpful for future effective interventions for understanding salt reduction. The trends of Relative search volumes (RSVs) for "salt reduction" and "salt reduction filtered" have significantly increased RSV in 2021 compared to 2004. Google Trends is an effective tool for salt reduction awareness research that provides large amounts of real-time search data.

Cigarette smoke induces mitochondrial DNA damage and activates cGAS-STING pathway: application to a biomarker for atherosclerosis.

Cigarette smoking is a major risk factor for atherosclerosis. We previously reported that DNA damage was accumulated in atherosclerotic plaque, and was increased in human mononuclear cells by smoking. As vascular endothelial cells are known to modulate inflammation, we investigated the mechanism by which smoking activates innate immunity in endothelial cells focusing on DNA damage. Furthermore, we sought to characterize the plasma level of cell-free DNA (cfDNA), a result of mitochondrial and/or genomic DNA damage, as a biomarker for atherosclerosis. Cigarette smoke extract (CSE) increased DNA damage in the nucleus and mitochondria in human endothelial cells. Mitochondrial damage induced minority mitochondrial outer membrane permeabilization, which was insufficient for cell death but instead led to nuclear DNA damage. DNA fragments, derived from the nucleus and mitochondria, were accumulated in the cytosol, and caused a persistent increase in IL-6 mRNA expression via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. cfDNA, quantified with quantitative PCR in culture medium was increased by CSE. Consistent with in vitro results, plasma mitochondrial cfDNA (mt-cfDNA) and nuclear cfDNA (n-cfDNA) were increased in young healthy smokers compared with age-matched nonsmokers. Additionally, both mt-cfDNA and n-cfDNA were significantly increased in patients with atherosclerosis compared with the normal controls. Our multivariate analysis revealed that only mt-cfDNA predicted the risk of atherosclerosis. In conclusion, accumulated cytosolic DNA caused by cigarette smoke and the resultant activation of the cGAS-STING pathway may be a mechanism of atherosclerosis development. The plasma level of mt-cfDNA, possibly as a result of DNA damage, may be a useful biomarker for atherosclerosis.

Angiotensin II Type 1 Receptor Blocker Prevents Abdominal Aortic Aneurysm Progression in Osteoprotegerin-Deficient Mice via Upregulation of Angiotensin (1-7).

Background Angiotensin II type 1 receptor blockers (ARBs) have been shown to limit the growth of abdominal aortic aneurysm (AAA), but their efficacy is controversial. This study aimed to investigate the molecular mechanism underlying the protective effect of ARBs against AAA progression. Methods and Results Olmesartan, an ARB, was administered to wild-type and osteoprotegerin-knockout (Opg-KO) mice starting 2 weeks before direct application of CaCl2 to aortas to induce AAA. The protective effect of olmesartan against AAA in wild-type and Opg-KO mice was compared at 6 weeks after AAA induction. Olmesartan prevented AAA progression in Opg-KO mice, including excessive aortic dilatation and collapse of tunica media, but not in wild-type mice. Deficiency of the Opg gene is known to cause excessive activation of the tumor necrosis factor-related apoptosis-inducing ligand-induced c-Jun N-terminal kinase/matrix metalloproteinase 9 pathway, resulting in prolonged AAA progression. Olmesartan attenuated the upregulation of phosphorylated c-Jun N-terminal kinase and matrix metalloproteinase 9 expression in the aortic wall of Opg-KO mice. In cultured vascular smooth muscle cells, tumor necrosis factor-related apoptosis-inducing ligand-induced c-Jun N-terminal kinase phosphorylation and matrix metalloproteinase 9 expression were inhibited by angiotensin (1-7), the circulating levels of which are increased by ARBs. Furthermore, administering an angiotensin (1-7) antagonist to Opg-KO mice diminished the protective effect of olmesartan against AAA progression. Conclusions Olmesartan prevented AAA progression in Opg-KO mice by upregulating angiotensin (1-7), suggesting that angiotensin (1-7) may be a key factor that mediates the protective effect of ARBs.

Role of DNA damage in the pathogenesis of atherosclerosis.

Atherosclerosis is a cause of coronary artery disease, abdominal aortic aneurysm, and stroke. The pathogenesis underlying atherosclerosis is complex but it is clear that inflammation plays a pivotal role. Inflammation in atherosclerosis is triggered by the recognition of intracellular contents released from damaged cells by pattern recognition receptors, and is therefore sterile and chronic. Because the DNA of these cells is damaged, cellular senescence is also involved in this inflammation. Here, we will discuss the emerging evidence of a relationship between DNA damage and inflammation in the pathogenesis of atherosclerosis, with a focus on intracellular events and cell fates that arise following DNA damage. Recent evidence will lead us to potential therapeutic targets and allow us to explore potential preventative and therapeutic strategies.

Hospitalizations for Cardiovascular Diseases During the Early Stage of the COVID-19 Pandemic in Japan.

Background: Although reductions in hospitalizations for myocardial infarction and heart failure have been reported during the period of COVID-19 pandemic restrictions, it is unclear how the overall number of hospitalizations for cardiovascular disease (CVD) treatment changed in the early stages of the pandemic. Methods and Results: We analyzed the records of 574 certified hospitals affiliated with the Japanese Circulation Society and retrieved data from April 2015 to March 2020. Records were obtained from the nationwide Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination database. A quasi-Poisson regression model was used to estimate the number of hospitalizations for CVD treatment. Between January and March 2020, when the number of COVID-19 cases was relatively low in Japan, the actual/estimated number of hospitalizations for acute CVD was 18,233/21,634 (84.3%), whereas the actual/estimated number of scheduled hospitalizations was 16,921/19,066 (88.7%). The number of hospitalizations for acute heart failure and scheduled hospitalizations for valvular disease and aortic aneurysm were 81.1%, 84.6%, and 83.8% of the estimated values, respectively. A subanalysis that considered only facilities without hospitalization restrictions did not alter the results for these diseases. Conclusions: The spread of COVID-19 was associated with a decreased number of hospitalizations for CVD in Japan, even in the early stages of the pandemic.

DNA Damage Induced by Radiation Exposure from Cardiac Catheterization.

Almost 40% of medical radiation exposure is related to cardiac imaging or intervention. However, the biological effects of low-dose radiation from medical imaging remain largely unknown. This study aimed to evaluate the effects of ionized radiation from cardiac catheterization on genomic DNA integrity and inflammatory cytokines in patients and operators.Peripheral mononuclear cells (MNCs) were isolated from patients (n = 51) and operators (n = 35) before and after coronary angiography and/or percutaneous coronary intervention. The expression of γH2AX, a marker for DNA double-strand breaks, was measured by immunofluorescence. Dicentric chromosomes (DICs), a form of chromosome aberrations, were assayed using a fluorescent in situ hybridization technique.In the patient MNCs, the numbers of γH2AX foci and DICs increased after cardiac catheterization by 4.5 ± 9.4-fold and 71 ± 122%, respectively (P < 0.05 for both). The mRNA expressions of interleukin (IL)-1α, IL-1ß, leukemia inhibitory factor, and caspase-1 were significantly increased by radiation exposure from cardiac catheterization. The increase in IL-1ß was significantly correlated with that of γH2AX, but not with the dose area product. In the operators, neither γH2AX foci nor the DIC level was changed, but IL-1ß mRNA was significantly increased. The protein expression of IκBα was significantly decreased in both groups.DNA damage was increased in the MNCs of patients, but not of operators, who underwent cardiac catheterization. Inflammatory cytokines were increased in both the patients and operators, presumably through NF-κB activation. Further efforts to reduce radiation exposure from cardiac catheterization are necessary for both patients and operators.

Impact of Tweeting Summaries by the Japanese Circulation Society Official Account on Article Viewership　- Pilot Trial.

BACKGROUND: The impact of promotional tweets from the official journal account (forCirculation JournalandCirculation Reports) on article viewership has not been thoroughly evaluated.Methods and Results:We retrospectively collected journal viewership data forCirculation JournalandCirculation Reportsfrom March 2021 to August 2021. We compared viewership between articles with (n=15) and without (n=250) tweets. After 1 : 4 propensity score matching (15 tweeted articles and 60 non-tweeted matched controls), journal viewership metrics within 7 days of the tweeting date (and the hypothetical tweeting date), was larger in tweeted articles than non-tweeted articles (median [interquartile range] Abstract page views 89 [60-104] vs. 18 [8-41]). CONCLUSIONS: This pilot study suggests a positive relationship between journal-posted promotional tweets and article viewership.

Sporadic endemicity of zoonotic Paragonimus in raccoon dogs and Japanese badgers from Miyazaki Prefecture, Japan.

Paragonimiasis is a zoonotic trematode infection caused by Paragonimus spp. To determine the recent status of Paragonimus infections in wild animals, this study investigated Paragonimus spp. in 39 raccoon dogs and 54 Japanese badgers from March 2019 to January 2021 in Miyazaki Prefecture, and examined metacercariae in freshwater crabs. Triploid P. westermani was found in one raccoon dog (2.6%), and metacercariae were recovered from Eriocheir japonica captured near the infected animal collected. One Japanese badger (1.9%) harbored P. skrjabini miyazakii; this prevalence was lower than the approximately 30% that was reported in the 1970s. Results indicated that zoonotic Paragonimus was sporadically prevalent in wild animals. Further investigation in various animals is awaited to elucidate current wildlife reservoirs for those Paragonimus.

Current Diversity Issues in Cardiovascular Workplaces in the Chugoku District　- Results From 2 Questionnaire Surveys.

Background: Various issues, such as gender diversity and overwork, need to be considered in cardiovascular workplaces. Here, we report the results of 2 questionnaire surveys conducted among members of the Chugoku branch of the Japanese Circulation Society. Methods and Results: The first questionnaire was posted to all 194 female members in 2018. Of the 73 respondents, 61.6% reported feeling that it would be difficult to continue in cardiovascular care. The second questionnaire was completed by participants of the Chugoku Regional Meeting in 2019. Of the 133 respondents, 42.4% reported difficulties continuing in cardiovascular care. Respondents reporting difficulties had a significantly lower mean age, a higher frequency of day and night shifts, and a higher rate of working >80 h/week than respondents who did not report such difficulties. In logistic regression analysis, working >80 h/week was the only independent factor associated with difficulties continuing in cardiovascular care (odds ratio 4.16; 95% confidence interval 1.46-11.9; P=0.008). Although 47.4% of respondents worked >960 h overtime per year (considered a risk factor for death from overwork), 59.6% of these respondents reported being satisfied with their current situation. Conclusions: In the Chugoku region, the work-life balance of medical personnel engaged in cardiovascular care has not been sufficiently secured. In order to promote diverse human resources, we need to recognize the current situation and continue to take countermeasures.

A Combination of Iohexol Treatment and Ionizing Radiation Exposure Enhances Kidney Injury in Contrast-Induced Nephropathy by Increasing DNA Damage.

Contrast media has been shown to induce nephropathy (i.e., contrast-induced nephropathy) after various types of radiological examinations. The molecular mechanism of contrast-induced nephropathy has been unclear. In this study, we investigated the mechanism of contrast-induced nephropathy by examining the effects of combined treatment of contrast medium and ionizing radiation on kidney cells in vitro and kidney tissue in vivo. In human renal tubular epithelium cells, immunofluorescence analysis revealed that iohexol increased the numbers of radiation-induced γH2AX nuclear foci. The numbers of γH2AX nuclear foci remained high at 24 h, suggesting that some radiation-induced double-strand breaks remain unrepaired in the presence of iohexol. We established a mouse model of contrast-induced nephropathy, then showed that iohexol and ionizing radiation synergistically reduced renal function and induced double-strand breaks. Importantly, iohexol induced significant macrophage accumulation and oxidative DNA damage in the kidneys of contrast-induced nephropathy model mice in the absence of ionizing radiation; these effects were amplified by ionizing radiation. The results suggest that underlying inflammation and oxidative DNA damage caused by iohexol contribute to the enhancement of radiation-induced double-strand breaks, leading to contrast-induced nephropathy.

S-1-Propenylcysteine promotes IL-10-induced M2c macrophage polarization through prolonged activation of IL-10R/STAT3 signaling.

Atherosclerosis is a chronic inflammatory disease that may lead to the development of serious cardiovascular diseases. Aged garlic extract (AGE) has been reported to ameliorate atherosclerosis, although its mode of action remains unclear. We found that AGE increased the mRNA or protein levels of arginase1 (Arg1), interleukin-10 (IL-10), CD206 and hypoxia-inducible factor 2α (HIF2α) and decreased that of CD68, HIF1α and inducible nitric oxide synthase in the aorta and spleen of apolipoprotein E knockout mice. We also found that S-1-propenylcysteine (S1PC), a characteristic sulfur compound in AGE, increased the level of IL-10-induced Arg1 mRNA and the extent of M2c-like macrophage polarization in vitro. In addition, S1PC increased the population of M2c-like macrophages, resulting in suppressed the population of M1-like macrophages and decreased lipopolysaccharide-induced production of pro-inflammatory cytokines. These effects were accompanied by prolonged phosphorylation of the IL-10 receptor α (IL-10Rα) and signal transducer and activator of transcription 3 (STAT3) that inhibited the interaction between IL-10Rα and Src homology-2-containing inositol 5'-phosphatase 1 (SHIP1). In addition, administration of S1PC elevated the M2c/M1 macrophage ratio in senescence-accelerated mice. These findings suggest that S1PC may help improve atherosclerosis due to its anti-inflammatory effect to promote IL-10-induced M2c macrophage polarization.