Sex Differences in Cardiovascular Disease-Related Hospitalization and Mortality in Japan　- Analysis of Health Records From a Nationwide Claim-Based Database, the Japanese Registry of All Cardiac and Vascular Disease (JROAD).

BACKGROUND: The prevalence of cardiovascular disease (CVD) is rising in Japan with its aging population, but there is a lack of epidemiological data on sex differences in CVD, including acute coronary syndrome (ACS), acute heart failure (AHF), and acute aortic disease.Methods and Results: This retrospective study analyzed data from 1,349,017 patients (January 2012-December 2020) using the Japanese Registry Of All Cardiac and Vascular Diseases database. ACS patients were youngest on average (70.5±12.9 years) and had the lowest female proportion (28.9%). AHF patients had the oldest mean age (79.7±12.0 years) and the highest proportion of females (48.0%). Acute aortic disease had the highest in-hospital mortality (26.1%), followed by AHF (11.5%) and ACS (8.9%). Sex-based mortality differences were notable in acute aortic disease, with higher male mortality in Stanford Type A acute aortic dissection (AAD) with surgery (males: 14.2% vs. females: 10.4%, P<0.001) and similar rates in Type B AAD (males: 6.2% vs. females: 7.9%, P=0.52). Aging was a universal risk factor for in-hospital mortality. Female sex was a risk factor for ACS and acute aortic disease but not for AHF or Types A and B AAD. CONCLUSIONS: Sex-based disparities in the CVD-related hospitalization and mortality within the Japanese national population have been highlighted for the first time, indicating the importance of sex-specific strategies in the management and understanding of these conditions.

Sex Differences in Bleeding Risk Associated With Antithrombotic Therapy Following Percutaneous Coronary Intervention.

Background: Antithrombotic therapy is crucial for secondary prevention of cardiovascular disease (CVD), but women with CVD may face increased bleeding complications post-percutaneous coronary intervention (PCI) under antithrombotic therapy. However, women are often underrepresented in clinical trials in this field, so evidence for sex-specific recommendations is lacking. Methods and Results: A search on PubMed was conducted for English-language articles addressing bleeding complications and antithrombotic therapy in women. Despite women potentially showing higher baseline platelet responsiveness than men, the clinical implications remain unclear. Concerning antiplatelet therapy post-PCI, although women have an elevated bleeding risk in the acute phase, no sex differences were observed in the chronic phase. However, women require specific considerations for factors such as age, renal function, and weight when determining the dose and duration of antiplatelet therapy. Regarding anticoagulation post-PCI, direct oral anticoagulants may pose a lower bleeding risk in women compared with warfarin. Concerning triple antithrombotic therapy (TAT) post-PCI for patients with atrial fibrillation, there is a lack of evidence on whether sex differences should be considered in the duration and regimen of TAT. Conclusions: Recent findings on sex differences in post-PCI bleeding complications did not provide enough evidence to recommend specific therapies for women. Further studies are needed to address this gap and recommend optimal antithrombotic therapy post-PCI for women.

Scoping Review of Screening and Assessment Tools for Social Determinants of Health in the Field of Cardiovascular Disease.

BACKGROUND: Despite the importance of implementing the concept of social determinants of health (SDOH) in the clinical practice of cardiovascular disease (CVD), the tools available to assess SDOH have not been systematically investigated. We conducted a scoping review for tools to assess SDOH and comprehensively evaluated how these tools could be applied in the field of CVD.Methods and Results: We conducted a systematic literature search of PubMed and Embase databases on July 25, 2023. Studies that evaluated an SDOH screening tool with CVD as an outcome or those that explicitly sampled or included participants based on their having CVD were eligible for inclusion. In addition, studies had to have focused on at least one SDOH domain defined by Healthy People 2030. After screening 1984 articles, 58 articles that evaluated 41 distinct screening tools were selected. Of the 58 articles, 39 (67.2%) targeted populations with CVD, whereas 16 (27.6%) evaluated CVD outcome in non-CVD populations. Three (5.2%) compared SDOH differences between CVD and non-CVD populations. Of 41 screening tools, 24 evaluated multiple SDOH domains and 17 evaluated only 1 domain. CONCLUSIONS: Our review revealed recent interest in SDOH in the field of CVD, with many useful screening tools that can evaluate SDOH. Future studies are needed to clarify the importance of the intervention in SDOH regarding CVD.

National Survey Identifying the Factors Affecting the Career Development of Cardiologists in Japan.

BACKGROUND: Equality in training opportunities, studying abroad, and satisfaction with work are not well investigated among Japanese cardiologists.Methods and Results: We studied cardiologists' career development using a questionnaire that was emailed to 14,798 cardiologists belonging to the Japanese Circulation Society (JCS) in September 2022. Feelings regarding equality in training opportunities, preferences for studying abroad, and satisfaction with work were evaluated with regard to cardiologists' age, sex, and other confounding factors. Survey responses were obtained from 2,566 cardiologists (17.3%). The mean (±SD) age of female (n=624) and male (n=1,942) cardiologists who responded to the survey was 45.6±9.5 and 50.0±10.6 years, respectively. Inequality in training opportunities was felt more by female than male cardiologists (44.1% vs. 33.9%) and by younger (<45 years old) than older (≥45 years old) (42.0% vs. 32.8%). Female cardiologists were less likely to prefer studying abroad (53.7% vs. 59.9%) and less satisfied with their work (71.3% vs. 80.8%) than male cardiologists. Increased feelings of inequality and lower work satisfaction were investigated among cardiologists who were young, had family care duties, and had no mentors. In the subanalysis, significant regional differences were found in cardiologists' career development in Japan. CONCLUSIONS: Female and younger cardiologists felt greater inequality in career development than male and older cardiologists. A diverse workplace may prompt equality in training opportunities and work satisfaction for both female and male cardiologists.

Effect of sacubitril/valsartan on natriuretic peptide in patients with compensated heart failure.

The time-dependent changes in the natriuretic peptide families during sacubitril/valsartan (S/V) treatment remain obscure in the Asian heart failure (HF) cohort. Eighty-one outpatients with compensated HF were analyzed. The patients were divided into two groups based on the administration of S/V (n = 42) or angiotensin converting enzyme inhibitor (ACE-I; n = 39). Changes to the natriuretic peptide families and the daily dose of loop diuretics were evaluated 3 and 6 months after the intervention. The atrial natriuretic peptide (ANP) level was significantly increased (102 [63-160] pg/mL to 283 [171-614] pg/mL [3 months]; 409 [210-726] pg/mL [6 months]) in the S/V group but not in the ACE-I group. The dose of furosemide was significantly decreased during the six-month follow-up period in the S/V group (40 [20-40] mg to 20 [10-20] mg) but not in the ACE-I group. A multivariate logistic regression model showed that the presence of persistent atrial fibrillation (AF) and HF with a preserved left ventricular ejection fraction (HFpEF) was independently associated with a high delta-ANP ratio (≥ 4.5 ANP value on the start date/ANP value at 6 months; the mean value was used as the cutoff value) (odds ratio [OR]: 4.649, 95% CI 1.032-20.952 and OR: 7.558, 95% CI 1.427-40.042). The plasma level of ANP was increased, and the loop diuretic dose was decreased by the addition of neprilysin inhibitor therapy in patients with compensated HF. In patients with HFpEF and complicated persistent AF, neprilysin inhibitor therapy was associated with an increase in ANP.

Angioscopic findings 1 year after percutaneous coronary intervention for chronic total occlusion.

BACKGROUND: Chronic total occlusion (CTO) is a high-risk factor for stent thrombosis, but little is known about the difference in neointimal healing between CTO and non-CTO lesions regarding implanted stents. We investigated factors affecting neointimal healing after stent implantation for CTO and non-CTO lesions using angioscopy. METHODS: We retrospectively evaluated 106 stents in 85 consecutive patients between March 2016 and July 2020. Their average age was 68 ±â€¯11 years, and participants (73 male and 12 female) underwent follow-up angiography and angioscopy 1 year after percutaneous coronary intervention (PCI). The stents (n = 106) were divided into three groups according to the lesion status at the previous PCI: CTO (n = 17), acute coronary syndrome (ACS) (n = 35), and stable coronary artery disease without CTO or non-CTO (n = 54). RESULTS: The neointimal stent coverage grade was significantly lower in the CTO and ACS groups than in the non-CTO group (0.4 ±â€¯0.5, 0.9 ±â€¯0.8, and 1.4 ±â€¯0.8, respectively, p < 0.001). Thrombi were significantly more frequent in CTO and ACS than in non-CTO (71 %, 51 %, and 15 %, respectively, p < 0.001). The yellow grade in CTO was comparable to that in ACS but significantly higher in CTO than in non-CTO (CTO vs. ACS vs. non-CTO 1.5 ±â€¯0.7, 1.4 ±â€¯0.6, and 0.9 ±â€¯0.7, respectively, p = 0.007). CONCLUSIONS: Delayed healing occurs in stents implanted for CTO lesions. Longer dual-antithrombotic therapy may be beneficial.

Adjunctive Catheter-Directed Thrombolysis during Primary PCI for ST-Segment Elevation Myocardial Infarction with High Thrombus Burden.

BACKGROUND: High coronary thrombus burden has been associated with unfavorable outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the optimal management of which has not yet been established. METHODS: We assessed the adjunctive catheter-directed thrombolysis (CDT) during primary percutaneous coronary intervention (PCI) in patients with STEMI and high thrombus burden. CDT was defined as intracoronary infusion of tissue plasminogen activator (t-PA; monteplase). RESULTS: Among the 1849 consecutive patients with STEMI, 263 had high thrombus burden. Moreover, 41 patients received t-PA (CDT group), whereas 222 did not receive it (non-CDT group). No significant differences in bleeding complications and in-hospital and long-term mortalities were observed (9.8% vs. 7.2%, p = 0.53; 7.3% vs. 2.3%, p = 0.11; and 12.6% vs. 17.5%, p = 0.84, CDT vs. non-CDT). In patients who underwent antecedent aspiration thrombectomy during PCI (75.6% CDT group and 87.4% non-CDT group), thrombolysis in myocardial infarction grade 2 or 3 flow rate after thrombectomy was significantly lower in the CDT group than in the non-CDT group (32.2% vs. 61.0%, p < 0.01). However, the final rates improved without significant difference (90.3% vs. 97.4%, p = 0.14). CONCLUSIONS: Adjunctive CDT appears to be tolerated and feasible for high thrombus burden. Particularly, it may be an option in cases with failed aspiration thrombectomy.

Effect of Gonadectomy and Angiotensin II Receptor Blockade in a Mouse Model of Isoproterenol-induced Cardiac Diastolic Dysfunction.

BACKGROUND: Although heart failure (HF) with preserved ejection fraction (HFpEF) is more common in postmenopausal women than in men, the effect of sex hormones on cardiac diastolic function remains unclear. We examined the effect of gonadectomy with or without the angiotensin receptor blocker olmesartan (Olm) in an isoproterenol (ISO) -induced mouse model of left ventricular hypertrophy (LVH) and cardiac diastolic dysfunction. METHODS: ISO or ISO with Olm were administered for 28 days in sham-operated male and female, castrated (CAS), and ovariectomized (OVX) mice. LV ejection fraction (EF) and E/A ratio were analyzed by echocardiography, and the LV and lung weight corrected by tibial length were used as indices of LVH and lung congestion, respectively. RESULTS: On echocardiography, systolic function did not differ between the four groups. LV/tibial length (TL) and Lung/TL significantly increased in all groups. The LV/TL ratio was lower in castrated-ISO vs. Male-Sham-ISO but did not differ between Female-Sham-ISO and OVX-ISO. However, the Lung/TL ratio of OVX-ISO was greater than that of Female-Sham-ISO. Olm prevented LV hypertrophy in all groups. The decrease in E/A and increase in lung weight were improved by Olm in Male-Sham and OVX-ISO but not in the other groups. CONCLUSION: These sex differences suggest that sex hormones play a pivotal role in modulating cardiac hypertrophy and diastolic dysfunction induced by chronic ß-adrenoceptor stimulation, and thus affect the therapeutic potential of angiotensin receptor blockade.

ß 3-Adrenergic Receptor Agonist Prevents Diastolic Dysfunction in an Angiotensin II-Induced Cardiomyopathy Mouse Model.

ß3-Adrenergic receptor expression is enhanced in the failing heart, but its functional effects are unclear. We tested the hypothesis that a ß3-agonist improves left ventricular (LV) performance in heart failure. We examined the chronic effects of a ß3-agonist in the angiotensin II (Ang II)-induced cardiomyopathy mouse model. C57BL/6J mice were treated with Ang II alone or Ang II + BRL 37344 (ß3-agonist, BRL) for 4 weeks. Systolic blood pressure in conscious mice was significantly elevated in Ang II and Ang II + BRL mice compared with control mice. Heart rate was not different among the three groups. Systolic performance parameters that were measured by echocardiography and an LV catheter were similar among the groups. LV end-diastolic pressure and end-diastolic pressure-volume relationships were higher in Ang II mice compared with control mice. However, the increase in these parameters was prevented in Ang II + BRL mice, which suggested improvement in myocardial stiffness by BRL. Pathologic analysis showed that LV hypertrophy was induced in Ang II mice and failed to be prevented by BRL. However, increased collagen I/III synthesis, cardiac fibrosis, and lung congestion observed in Ang II mice were inhibited by BRL treatment. The cardioprotective benefits of BRL were associated with downregulation of transforming growth factor-ß1 expression and phosphorylated-Smad2/3. Chronic infusion of a ß3-agonist has a beneficial effect on LV diastolic function independent of blood pressure in the Ang II-induced cardiomyopathy mouse model. SIGNIFICANCE STATEMENT: Chronic infusion of a ß3-adrenergic receptor agonist attenuates cardiac fibrosis and improves diastolic dysfunction independently of blood pressure in an angiotensin II-induced hypertensive mouse model. This drug might be an effective treatment of heart failure with preserved ejection fraction.

Relationships between the serum cholesterol levels, production of monocyte proinflammatory cytokines and long-term prognosis in patients with chronic heart failure.

OBJECTIVE: Low serum cholesterol is associated with a poor prognosis in patients with chronic heart failure (CHF). However, the relationships between the serum cholesterol level, production of monocyte proinflammatory cytokines and long-term prognosis in CHF patients remain unclear. METHODS: A total of 95 CHF patients who had not been treated with statins and had a mean left ventricular ejection fraction of 26.0±6.0% were examined. Peripheral blood mononuclear cells (PBMCs) were isolated, and the production of monocyte tumor necrosis factor (TNF)-α and interleukin (IL)-6 was measured and expressed as the mean ± SD (pg/mL/10(6) PBMCs). RESULTS: The production of monocyte TNF-α and IL-6 was found to be significantly and negatively associated with the serum low-density lipoprotein (LDL)-cholesterol level (TNF-α: r=-0.515, p<0.001, IL-6: r=-0.419, p<0.001). During a median follow-up of 66.0 months, 49 patients developed cardiac events, including 21 cardiac deaths and 28 readmissions for worsening CHF. A multivariate Cox hazard analysis showed that a monocyte TNF-α level of ≥4.9 pg/mL/10(6) PBMCs [hazard ratio (HR) 187.38, 95% confidence interval (CI) 7.92-4,434.94, p=0.001] and LDL-cholesterol level of <120 mg/dL (HR 9.41, 95% CI 1.02-86.66, p=0.048) were independently associated with the incidence of cardiac events. CONCLUSION: Low LDL-cholesterol and the upregulation of monocyte proinflammatory cytokine production are both significantly and independently associated with poor outcomes in CHF patients.

Hepatocyte growth factor overexpression in the nervous system enhances learning and memory performance in mice.

Hepatocyte growth factor (HGF) and its receptor, c-Met, play pivotal roles in the nervous system during development and in disease states. However, the physiological roles of HGF in the adult brain are not well understood. In the present study, to assess its role in learning and memory function, we used transgenic mice that overexpress HGF in a neuron-specific manner (HGF-Tg) to deliver HGF into the brain without injury. HGF-Tg mice displayed increased alternation rates in the Y-maze test compared with age-matched wild-type (WT) controls. In the Morris water maze (MWM) test, HGF-Tg mice took less time to find the platform on the first day, whereas the latency to escape to the hidden platform was decreased over training days compared with WT mice. A transfer test revealed that the incidence of arrival at the exact location of the platform was higher for HGF-Tg mice compared with WT mice. These results demonstrate that overexpression of HGF leads to an enhancement of both short- and long-term memory. Western blot analyses revealed that the levels of N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B, but not NR1, were increased in the hippocampus of HGF-Tg mice compared with WT controls, suggesting that an upregulation of NR2A and NR2B could represent one mechanism by which HGF enhances learning and memory performance. These results demonstrate that modulation of learning and memory performance is an important physiological function of HGF that contributes to normal CNS plasticity, and we propose HGF as a novel regulator of higher brain functions.

Overexpression of HGF attenuates the degeneration of Purkinje cells and Bergmann glia in a knockin mouse model of spinocerebellar ataxia type 7.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder associated with cerebellar neurodegeneration caused by expansion of a CAG repeat in the ataxin-7 gene. Hepatocyte growth factor (HGF), a pleiotrophic growth factor, displays highly potent neurotrophic activities on cerebellar neurons. A mutant c-met/HGF receptor knockin mouse model has revealed a role for HGF in the postnatal development of the cerebellum. The present study was designed to elucidate the effect of HGF on cerebellar neurodegeneration in a knockin mouse model of SCA7 (SCA7-KI mouse). SCA7-KI mice were crossed with transgenic mice overexpressing HGF (HGF-Tg mice) to produce SCA7-KI/HGF-Tg mice that were used to examine the phenotypic differences following HGF overexpression. The Purkinje cellular degeneration is thought to occur via cell-autonomous and non-cell autonomous mechanisms mediated by a reduction of glutamate transporter levels in Bergmann glia. The Purkinje cellular degeneration and reduced expression of glutamate transporters in the cerebellum of SCA7-KI mice were largely attenuated in the SCA7-KI/HGF-Tg mice. Moreover, phenotypic impairments exhibited by SCA7-KI mice during rotarod tests were alleviated in SCA7-KI/HGF-Tg mice. The bifunctional nature of HGF on both Purkinje cells and Bergmann glia highlight the potential therapeutic utility of this molecule for the treatment of SCA7 and related disorders.