Rationale and design of an investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized trial to evaluate the effects of finerenone on vascular stiffness and cardiorenal biomarkers in type 2 diabetes and chronic kidney disease (FIVE-STAR).

BACKGROUND: The overactivation of mineralocorticoid receptor (MR) plays a key pathological role in the progression of cardiovascular and renal diseases by promoting pro-inflammatory and pro-fibrotic signaling. Recently, it has been found that finerenone, a novel nonsteroidal selective MR antagonist, can robustly improve cardiorenal outcomes in patients with type 2 diabetes (T2D) and a wide spectrum of chronic kidney disease (CKD). However, the mechanisms underlying the cardiorenal benefits of finerenone are poorly understood. Further, whether the clinical benefits are mediated by an improvement in vascular stiffness is not confirmed. Therefore, the current study aims to evaluate the effects of finerenone on vascular stiffness as assessed using cardio ankle vascular index (CAVI) and relevant cardiorenal biomarkers in patients with T2D and CKD. METHODS: The Effects of Finerenone on Vascular Stiffness and Cardiorenal Biomarkers in Type 2 Diabetes and Chronic Kidney Disease (FIVE-STAR) is an ongoing, investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized clinical trial in Japan. Its target sample size is 100 subjects. Recruitment will be performed from September 2023 to July 2024. After obtaining informed consent, eligible participants with T2D and CKD (25 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 90 mL/min/1.73 m2 and 30 mg/g Cr ≤ urinary albumin-to-creatinine ratio [UACR] < 3500 mg/g Cr) will be equally randomized to receive 24-week treatment with either finerenone (starting dose at 10 mg once daily in participants with a baseline eGFR < 60 mL/min/1.73 m2 or at 20 mg once daily in those with a baseline eGFR ≥ 60 mL/min/1.73 m2) or dose-matched placebo. The primary endpoint is the change from baseline in CAVI at 24 weeks. The secondary endpoints are changes from baseline in UACR at 12 and 24 weeks and relevant serum and urinary biomarkers at 24 weeks. As an exploratory endpoint, proteomic analysis using the Olink® Target 96 panels will be also performed. DISCUSSION: FIVE-STAR is the first trial evaluating the therapeutic impact of finerenone on vascular stiffness and relevant cardiorenal biomarkers in patients with T2D and CKD. This study will provide mechanistic insights on the clinical benefits of finerenone based on recent cardiovascular and renal outcome trials. Trial registration Unique Trial Number, NCT05887817 ( https://clinicaltrials.gov/ct2/show/NCT05887817 ) and jRCTs021230011 ( https://jrct.niph.go.jp/latest-detail/jRCTs021230011 ).

Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial.

BACKGROUNDS/AIM: Sodium glucose co-transporter 2 inhibitors promote osmotic/natriuretic diuresis and reduce excess fluid volume, and this improves cardiovascular outcomes, including hospitalization for heart failure. We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD). METHODS: The study was a post-hoc analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24 weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10 mg once daily, n = 52) and placebo (n = 53) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24 weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration. RESULTS: In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by - 2.23% (95% CI - 5.72 to 1.25) at week 4, - 8.07% (- 12.76 to - 3.37) at week 12, and - 5.60% (- 9.87 to - 1.32) at week 24; eEV by - 70.3 mL (95% CI - 136.8 to - 3.8) at week 4, - 135.9 mL (- 209.6 to - 62.3) at week 12, and - 144.4 mL (- 226.3 to - 62.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r = 0.351, p = 0.015), but not with change in eEV. CONCLUSIONS: Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24 weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.

Comparison of the clinical effect of empagliflozin on glycemic and non-glycemic parameters in Japanese patients with type 2 diabetes and cardiovascular disease treated with or without baseline metformin.

BACKGROUND: The most recent treatment guidelines for type 2 diabetes (T2D) recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors should be considered preferentially in patients with T2D with either a high cardiovascular risk or with cardiovascular disease (CVD), regardless of their diabetes status and prior use of conventional metformin therapy. Whether the therapeutic impact of SGLT2 inhibitors on clinical parameters differs according to the use of metformin therapy however remains unclear. METHODS: The study was a post hoc analysis of the EMBLEM trial (UMIN000024502). All participants (n = 105; women 31.4%; mean age 64.8 years) had both T2D and CVD and were randomized to either 24 weeks of empagliflozin 10 mg daily or placebo. Analysis of the data assessed the effect of empagliflozin on changes from baseline to 24 weeks in glycemic and non-glycemic clinical parameters, according to the baseline use of metformin. RESULTS: Overall, 53 (50.5%) patients received baseline metformin. In the 52 patients treated with empagliflozin (48.1% with baseline metformin), the decrease in systolic blood pressure from baseline levels was greater in patients receiving metformin, compared to that observed in metformin-naïve patients (group difference - 8.5 [95% confidence interval (CI) - 17.7 to 0.6 mmHg], p = 0.066). Reduction in body mass index (BMI) was significantly greater in patients receiving baseline metformin, relative to nonusers (- 0.54 [95% CI - 1.07 to - 0.01] kg/m2, p = 0.047). The group ratio (baseline metformin users vs. nonusers) of proportional changes in the geometric mean of high-sensitivity Troponin-I (hs-TnI) was 0.74 (95% CI 0.59 to 0.92, p = 0.009). No obvious differences were observed in glycemic parameters (fasting plasma glucose, glycohemoglobin, and glycoalbumin) between the baseline metformin users and nonusers. CONCLUSION: Our findings suggest 24 weeks of empagliflozin treatment was associated with an improvement in glycemic control, irrespective of the baseline use of metformin therapy. The effects of empagliflozin on reductions in BMI and hs-TnI were more apparent in patients who received baseline metformin therapy, compared to that observed in metformin-naïve patients. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.

Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure: a sub analysis of the CANDLE trial.

BACKGROUND: Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline. METHODS: Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function. RESULTS: The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89-1.08) in the canagliflozin group and 1.07 (95% CI 0.97-1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82-1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e') showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e' < 4.7 cm/s indicated there was an association with lower NT-proBNP levels in the canagliflozin group compared with that in the glimepiride group (ratio of change with canagliflozin/glimepiride (0.83, 95% CI 0.66-1.04). CONCLUSIONS: In the subgroup with a lower LV diastolic function, canagliflozin showed a trend of reduced NT-pro BNP levels compared to that observed with glimepiride. This study suggests that the beneficial effects of canagliflozin treatment may be different in subgroups classified by the severity of LV diastolic dysfunction.

Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: A randomized, controlled trial.

BACKGROUND: An elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. METHODS AND FINDINGS: The study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10-60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat - control], -0.007 mm [95% confidence interval (CI) -0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, -0.016 mm [95% CI -0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI -0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI -0.5% to 3.3%] in the control group (n = 193); mean between-group difference, -0.2% [95% CI -2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI -0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, -2.62 mg/dL [95% CI -2.86 mg/dL to -2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia. CONCLUSIONS: In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry UMIN000012911.

Questionnaire in patients with aborted sudden cardiac death due to coronary spasm in Japan.

OBJECTIVES: We investigated the medical or mechanical therapy, and the present knowledge of Japanese cardiologists about aborted sudden cardiac death (ASCD) due to coronary spasm. METHODS: A questionnaire was developed regarding the number of cases of ASCD, implantable cardioverter-defibrillator (ICD), and medical therapy in ASCD patients due to coronary spasm. The questionnaire was sent to the Japanese general institutions at random in 204 cardiology hospitals. RESULTS: The completed surveys were returned from 34 hospitals, giving a response rate of 16.7%. All SCD during the 5 years was observed in 5726 patients. SCD possibly due to coronary spasm was found in 808 patients (14.0%) and ASCD due to coronary spasm was observed in 169 patients (20.9%). In 169 patients with ASCD due to coronary spasm, one or two coronary vasodilators was administered in two-thirds of patients [113 patients (66.9%)], while more than 3 coronary vasodilators were found in 56 patients (33.1%). ICD was implanted in 117 patients with ASCD due to coronary spasm among these periods including 35 cases with subcutaneous ICD. Majority of cause of ASCD was ventricular fibrillation, whereas pulseless electrical activity was observed in 18 patients and complete atrioventricular block was recognized in 7 patients. Mean coronary vasodilator number in ASCD patients with ICD was significantly lower than that in those without ICD (2.1 ± 0.9 vs. 2.6 ± 1.0, p < 0.001). Although 16 institutions thought that the spasm provocation tests under the medications had some clinical usefulness of suppressing the next fatal arrhythmias, spasm provocation tests under the medication were performed in just 4 institutions. CONCLUSIONS: In the real world, there was no fundamental strategy for patients with ASCD due to coronary spasm. Each institution has each strategy for these patients. Cardiologists should have the same strategy and the same knowledge about ASCD patients due to coronary spasm in the future.

History of gastroesophageal reflux disease in patients with suspected coronary artery disease.

It is well known that patients with gastroesophageal reflux disease (GERD) experience GERD-related chest pain, but little is known about the relationship between GERD and coronary artery disease (CAD). We evaluated medical history of GERD in patients with suspected CAD and its association with types of CAD. We enrolled 236 patients who underwent coronary angiography (CAG). We assessed past medical history of each patient, making note of esophageal or stomach diseases such as GERD including reflux esophagitis and non-erosive reflux disease. The patients were divided into the following three subgroups based on the CAG results. Group I, patients with o-CAD (> 50% stenosis with ischemic findings, n = 141); Group II, patients with vasospastic angina (VSA, with positive spasm provocation test without organic coronary stenosis, n = 52); and Group III, patients without organic coronary stenosis or VSA (n = 43). Group I included more men than women (p < 0.001) and the frequencies of smoking, lipid disorders, and diabetes mellitus in this group were higher than those in the other groups (p < 0.01). The frequency of medical history of GERD was significantly higher in Group II (21%) than in Group I (3%) or Group III (7%, p < 0.0001). Logistic regression analysis showed that a medical history of GERD (OR 7.8; p < 0.01) was one of the factors associated with the presence of VSA. Our findings showed that a medical history of GERD was frequently observed in approximately one-fifth of patients with VSA, indicating that VSA may be present in patients with chest pain and a medical history of GERD.

Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD). SGLT2 inhibitors are known to not only decrease plasma glucose levels, but also favorably modulate a wide range of metabolic and hemodynamic disorders related to CV pathways. Although some experimental studies revealed a beneficial effect of SGLT2 inhibitors on atherosclerosis, there is a paucity of clinical data showing that they can slow the progression of atherosclerosis in patients with T2DM. Therefore, the EMBLEM trial was designed to investigate whether empagliflozin treatment can improve endothelial function, which plays a pivotal role in the pathogenesis of atherosclerosis, in patients with T2DM and established CVD. METHODS: The EMBLEM trial is an ongoing, prospective, multicenter, placebo-controlled double-blind randomized, investigator-initiated clinical trial in Japan. A total of 110 participants with T2DM (HbA1c range 6.0-10.0%) and with established CVD will be randomized (1:1) to receive either empagliflozin 10 mg once daily or a placebo. The primary endpoint of the trial is change in the reactive hyperemia (RH)-peripheral arterial tonometry-derived RH index at 24 weeks from baseline. For comparison of treatment effects between the treatment groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for the following allocation factors: HbA1c (<7.0 or ≥7.0%), age (<65 or ≥65 years), systolic blood pressure (<140 or ≥140 mmHg), and current smoking status (nonsmoker or smoker). Key secondary endpoints include the change from baseline for other vascular-related markers such as arterial stiffness, sympathetic nervous activity, and parameters of cardiac and renal function. Importantly, serious adverse effects independently on the causal relationship to the trial drugs and protocol will be also evaluated throughout the trial period. DISCUSSION: EMBLEM is the first trial to assess the effect of empagliflozin on endothelial function in patients with T2DM and established CVD. Additionally, mechanisms associating empagliflozin-mediated actions with endothelial function and other CV markers will be evaluated. Thus, the trial is designed to elucidate potential mechanisms by which empagliflozin protects CV systems and improves CV outcomes. Trial registration Unique Trial Number, UMIN000024502 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028197 ).

Rationale and design of a multicenter randomized study for evaluating vascular function under uric acid control using the xanthine oxidase inhibitor, febuxostat: the PRIZE study.

BACKGROUND: Xanthine oxidase inhibitors are anti-hyperuricemic drugs that decrease serum uric acid levels by inhibiting its synthesis. Xanthine oxidase is also recognized as a pivotal enzyme in the production of oxidative stress. Excess oxidative stress induces endothelial dysfunction and inflammatory reactions in vascular systems, leading to atherosclerosis. Many experimental studies have suggested that xanthine oxidase inhibitors have anti-atherosclerotic effects by decreasing in vitro and in vivo oxidative stress. However, there is only limited evidence on the clinical implications of xanthine oxidase inhibitors on atherosclerotic cardiovascular disease in patients with hyperuricemia. We designed the PRIZE study to evaluate the effects of febuxostat on a surrogate marker of cardiovascular disease risk, ultrasonography-based intima-media thickness of the carotid artery in patients with hyperuricemia. METHODS: The study is a multicenter, prospective, randomized, open-label and blinded-endpoint evaluation (PROBE) design. A total of 500 patients with asymptomatic hyperuricemia (uric acid >7.0 mg/dL) and carotid intima-media thickness ≥1.1 mm will be randomized centrally to receive either febuxostat (10-60 mg/day) or non-pharmacological treatment. Randomization is carried out using the dynamic allocation method stratified according to age (<65, ≥65 year), gender, presence or absence of diabetes mellitus, serum uric acid (<8.0, ≥8.0 mg/dL), and carotid intima-media thickness (<1.3, ≥1.3 mm). In addition to administering the study drug, we will also direct lifestyle modification in all participants, including advice on control of body weight, sleep, exercise and healthy diet. Carotid intima-media thickness will be evaluated using ultrasonography performed by skilled technicians at a central laboratory. Follow-up will be continued for 24 months. The primary endpoint is percentage change in mean intima-media thickness of the common carotid artery 24 months after baseline, measured by carotid ultrasound imaging. CONCLUSIONS: PRIZE will be the first study to provide important data on the effects of febuxostat on atherosclerosis in patients with asymptomatic hyperuricemia. Trial Registration Unique trial Number, UMIN000012911 ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000015081&language=E ).

Rationale and design of a multicenter randomized controlled study to evaluate the preventive effect of ipragliflozin on carotid atherosclerosis: the PROTECT study.

BACKGROUND: Type 2 diabetes mellitus is associated strongly with an increased risk of micro- and macro-vascular complications, leading to impaired quality of life and shortened life expectancy. In addition to appropriate glycemic control, multi-factorial intervention for a wide range of risk factors, such as hypertension and dyslipidemia, is crucial for management of diabetes. A recent cardiovascular outcome trial in diabetes patients with higher cardiovascular risk demonstrated that a SGLT2 inhibitor markedly reduced mortality, but not macro-vascular events. However, to date there is no clinical evidence regarding the therapeutic effects of SGLT2 inhibitors on arteriosclerosis. The ongoing PROTECT trial was designed to assess whether the SGLT2 inhibitors, ipragliflozin, prevented progression of carotid intima-media thickness in Japanese patients with type 2 diabetes mellitus. METHODS: A total of 480 participants with type 2 diabetes mellitus with a HbA1c between 6 and 10 % despite receiving diet/exercise therapy and/or standard anti-diabetic agents for at least 3 months, will be randomized systematically (1:1) into either ipragliflozin or control (continuation of conventional therapy) groups. After randomization, ipragliflozin (50-100 mg once daily) will be added on to the background therapy in participants assigned to the ipragliflozin group. The primary endpoint of the study is the change in mean intima-media thickness of the common carotid artery from baseline to 24 months. Images of carotid intima-media thickness will be analyzed at a central core laboratory in a blinded manner. The key secondary endpoints include the change from baseline in other parameters of carotid intima-media thickness, various metabolic parameters, and renal function. Other cardiovascular functional tests are also planned for several sub-studies. DISCUSSION: The PROTECT study is the first to assess the preventive effect of ipragliflozin on progression of carotid atherosclerosis using carotid intima-media thickness as a surrogate marker. The study has potential to clarify the protective effects of ipragliflozin on atherosclerosis. Trial registration Unique Trial Number, JPRN/UMIN000018440 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021348 ).

Do changes in intracoronary pressure aid coronary spasm diagnosis using the spasm provocation test?

BACKGROUND: Although the spasm provocation test (SPT) can diagnose coronary spasms, it would be helpful if it could also predict their occurrence. AIM: To investigate whether coronary spasms can be predicted using changes in intracoronary artery pressure measured using a pressure wire during the SPT. METHODS: Seventy patients underwent SPTs with pressure-wire measurement of intracoronary artery pressure. During each SPT, the pressure wire was advanced into the distal portion of the right coronary artery (RCA) and left anterior descending coronary artery, and the ratio of intracoronary pressure to aortic pressure (Pd/Pa) was monitored. Coronary spasm was defined as an arterial narrowing of > 90% in response to the administration of acetylcholine (ACh), with chest symptoms and/or ischemic electrocardiographic changes. ACh was administered to the RCA at low, moderate, or high doses of 20, 50, or 80 µg, respectively, and to the left coronary artery (LCA) at low, moderate, or high doses of 50, 100, or 200 µg, respectively. Coronary arteries with coronary spasms at low doses of ACh were defined as group L, and those with coronary spasms at moderate or high doses were defined as group MH. Those who did not occur coronary spasms at any ACh dose were designated as group N. RESULTS: Among the 132 coronary arteries assessed using a pressure wire, there were 49 in group N, 25 in group L, and 58 in group MH. Baseline Pd/Pa was the lowest in group L (P = 0.001). The decrease in the Pd/Pa between baseline to low doses of ACh was lower in group MH than in group N (P < 0.001). A receiver-operating characteristics analysis showed that the cutoff baseline Pd/Pa value for predicting group L was 0.95, with a sensitivity of 0.600 (15/25) and a specificity of 0.713 (76/107) and that the cutoff value of Pd/Pa from baseline to low doses of ACh for predicting group MH was -0.04, with a sensitivity of 0.741 (43/58) and a specificity of 0.694 (34/49). CONCLUSION: These findings suggest that indices of intracoronary pressure during SPT may be useful means for predicting the occurrence of coronary spasms.

Factors Contributing to Coronary Microvascular Dysfunction in Patients with Angina and Non-Obstructive Coronary Artery Disease.

BACKGROUND: Coronary microvascular dysfunction (CMD), characterised by a reduced coronary flow reserve (CFR) or an increased index of microcirculatory resistance (IMR), has received considerable attention as a cause of chest pain in recent years. However, the risks and causes of CMD remain unclear; therefore, effective treatment strategies have not yet been established. Heart failure or coronary artery disease (CAD) is a risk factor for CMD, with a higher prevalence among women. However, the other contributing factors remain unclear. In this study, we assessed the risk in patients with angina and non-obstructive coronary artery disease (ANOCA), excluding those with heart failure or organic stenosis of the coronary arteries. Furthermore, we analysed whether the risk of CMD differed according to component factors and sex. METHODS: This study included 84 patients with ANOCA (36 men and 48 women; mean age, 63 years) who underwent coronary angiography and functional testing (CFT). The CFT included a spasm provocation test (SPT), followed by a coronary microvascular function test (CMVF). In the SPT, patients were mainly provoked by acetylcholine (ACh), and coronary spasm was defined as >90% transient coronary artery constriction on coronary angiography, accompanied by chest pain or ischaemic changes on electrocardiography. In 15 patients (18%) with negative ACh provocation, ergonovine maleate (EM) was administered as an additional provocative drug. In the CMVF, a pressure wire was inserted into the left anterior descending coronary artery using intravenous adenosine triphosphate, and the CFR and IMR were measured using previously described methods. A CFR < 2.0 or IMR ≥ 25 was indicative of CMD. The correlations between various laboratory indices and CMD and its components were investigated, and logistic regression analysis was performed, focusing on factors where p < 0.05. RESULTS: Of the 84 patients, a CFR < 2.0 was found in 22 (26%) and an IMR ≥ 25 in 40 (48%) patients, with CMD identified in 46 (55%) patients. CMD was correlated with smoking (p = 0.020) and the use of EM (p = 0.020). The factors that correlated with a CFR < 2.0 included the echocardiograph index E/e' (p = 0.013), which showed a weak but positive correlation with the CFR (r = 0.268, p = 0.013). Conversely, the factors correlated with an IMR ≥ 25 included RAS inhibitor usage (p = 0.018) and smoking (p = 0.042). Assessment of the risk of CMD according to sex revealed that smoking (p = 0.036) was the only factor associated with CMD in men, whereas the left ventricular mass index (p = 0.010) and low glycated haemoglobin levels (p = 0.012) were associated with CMD in women. CONCLUSIONS: Our results indicated that smoking status and EM use were associated with CMD. The risk of CMD differed between the two CMD components and sex. Although these factors should be considered when treating CMD, smoking cessation remains important. In addition, CMD assessment should be performed carefully when EM is used after ACh provocation. Further validation of our findings using prospective studies and large registries is warranted.

Clinical Characteristics and Major Adverse Cardiovascular Events in Diabetic and Non-Diabetic Patients with Vasospastic Angina.

Purpose: The clinical background and prognostic impact of diabetes mellitus (DM) on vasospastic angina (VSA) are unclear; thus, in this retrospective study, we investigated whether they differ based on the presence or absence of DM in patients with VSA. Patients and Methods: We included 272 Japanese patients with VSA diagnosed by coronary angiography (CAG) and the spasm provocation test (SPT). The diagnosis of DM was determined by measuring fasting blood glucose and hemoglobin A1C and by the patient's current oral medications. On CAG, the presence of atherosclerotic lesions (20%-50%) was checked. On SPT, the coronary spasm was defined as transient coronary vasoconstriction >90% on CAG, accompanied by chest symptoms and/or ST-T changes. Focal spasm was defined as coronary spasm occurring within one segment of the American Heart Association classification on CAG. Blood and urine tests and vascular endothelial function were also evaluated when possible. A major adverse cardiovascular event (MACE), which is defined as cardiac mortality and rehospitalization due to cardiovascular illness, was the basis for determining the prognosis. Results: There were 49 patients (18%) in the DM group and 223 (82%) in the non-DM group. No significant differences in urinary albumin levels and peripheral vascular function were between groups. On CAG, atherosclerotic lesions were observed significantly more frequently in the DM group (63% vs 46%; P = 0.028). Results of SPT showed a trend toward fewer focal spasms in the DM group (24% vs 39%; P = 0.072). No significant differences in MACE were noted between groups in the primary analysis of DM, whereas sub-analyses of focal spasms showed lower MACE-free survival in the DM group (P = 0.042). Conclusion: The study results support the hypothesis that DM associated with VSA should be treated appropriately, especially in cases of focal spasm, which may require more attention in treatment.

Blood pressure reduction with empagliflozin in Japanese patients with type 2 diabetes and cardiovascular diseases: a post-hoc sub-analysis of the placebo-controlled randomized EMBLEM trial.

Detailed effect of sodium-glucose cotransporter 2 inhibitors on blood pressure (BP) in Japanese patients with type 2 diabetes (T2D) at a high risk of cardiovascular disease (CVD) is not fully understood. In this post-hoc sub-analysis of placebo-controlled randomized EMBLEM trial for Japanese patients with T2D and CVD, 105 participants (empagliflozin N = 52, placebo N = 53) were included, and office systolic/diastolic BPs and mean arterial pressure (MAP) over 24 weeks were estimated using mixed-effects models for repeated measures. Empagliflozin therapy, compared to placebo, reduced systolic/diastolic BPs (mean group difference in change from baseline to week 24; -5.9 [95% confidence interval (CI), -10.4 to -1.4] mmHg/-2.9 [95% CI, -6.2 to 0.4] mmHg) and MAP ( - 3.8 [95% CI, -7.0 to -0.7] mmHg). The systolic BP reduction was almost consistent across differing background clinical characteristics and usage status of anti-hypertensive medications.

Effects of ipragliflozin on left ventricular diastolic function in patients with type 2 diabetes: A sub-analysis of the PROTECT trial.

BACKGROUND: We hypothesized that the beneficial effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on diastolic function might depend on baseline left ventricular (LV) systolic function. METHODS: To investigate the effects of SGLT2 inhibitors on LV diastolic function in patients with type 2 diabetes mellitus (T2DM), we conducted a post-hoc sub-study of the PROTECT trial, stratifying the data according to LV ejection fraction (LVEF) at baseline. After excluding patients without echocardiographic data at baseline or 24 months into the PROTECT trial, 31 and 38 patients with T2DM from the full analysis dataset of the PROTECT trial who received ipragliflozin or no SGLT2 inhibitor (control), respectively, were included. The primary endpoint was a comparison of the changes in echocardiographic parameters and N-terminal pro-brain natriuretic peptide levels from baseline to 24 months between the two groups stratified according to baseline LVEF. RESULTS: Differences in diastolic functional parameters (e' and E/e') were noted between the two groups. Among the subgroups defined according to median LVEF values, those with higher LVEF (≥60 %) who received ipragliflozin appeared to have a higher e' and lower E/e' than did those who received the standard of care with no SGLT2 inhibitor, indicating longitudinal improvements between baseline and follow up (p = 0.001 and 0.016, respectively). CONCLUSIONS: Ipragliflozin generally improved LV diastolic function in patients with type 2 diabetes, the extent of this improvement might appear to vary with LV systolic function.

Flow-mediated vasodilation and anatomical variation of the brachial artery (double brachial artery) in healthy subjects and patients with cardiovascular disease.

BACKGROUND: The purpose of this study was to evaluate the effect of anatomical variation of the brachial artery on flow-mediated vasodilation (FMD) in healthy subjects and patients with cardiovascular disease (CVD). METHODS AND RESULTS: There was no significant difference in the prevalence of double brachial artery between healthy subjects (6.1%) and patients with CVD (6.5%). In healthy subjects, FMD was larger in a single brachial artery than in large and small vessels of a double brachial artery (7.2±3.4% vs. 4.7±3.3% and 4.5±2.5%, P<0.01, respectively). In patients with CVD, there were no significant differences in FMD among a single brachial artery, large vessel of a double brachial artery and small vessel of a double brachial artery (3.3±1.4%, 3.1±2.3% and 3.6±2.1%). FMD in a single brachial artery was smaller in patients with CVD than in healthy subjects. There were no significant differences in FMD in the large vessel of a double brachial artery between the 2 groups or in the small vessel of a double brachial artery between the 2 groups. Nitroglycerine-induced vasodilation was similar in all arteries in healthy subjects and patients with CVD. CONCLUSIONS: When measuring FMD, the existence of a double brachial artery should be checked. FMD measured in a double brachial artery may be underestimated in healthy subjects.

Clinical Characteristics and Prognosis of Patients with Vasospastic Angina Subjected to the Spasm Provocation Test and the Unavoidable Use of Nitroglycerin.

Background: Multi-vessel spasm (MVS) has a prognostic impact in patients with vasospastic angina (VSA). Thus, the presence of coronary spasm in both the left coronary artery (LCA) and right coronary artery (RCA) should be assessed through the spasm provocation test (SPT). Nitroglycerin (NTG) is used to avoid SPT-related complications; however, this unavoidable use of NTG may decrease the detection of MVS. Therefore, we investigated the frequency of the unavoidable use of NTG during SPT and clarified the clinical characteristics in patients with VSA who underwent the unavoidable use of NTG during STP. Methods: A total of 141 patients with positive SPT were evaluated. A positive SPT was defined as > 90% constriction in epicardial coronary arteries in response to acetylcholine, accompanied by the usual chest symptoms and/or ischaemic ST-T changes on electrocardiography. When a coronary spasm occurred, we usually wait for the spontaneous relief of the coronary spasm. However, if a prolonged coronary spasm or unstable haemodynamics occurred, 0.3 mg NTG was administered intracoronarily to promptly relieve the coronary spasm and this was defined as the unavoidable use of NTG. Even when the unavoidable use of NTG was administered in one coronary artery, an additional SPT was performed on another coronary artery. If a coronary spasm occurred in another coronary artery, a positive SPT was diagnosed. In contrast, if a coronary spasm was not induced after the unavoidable use of NTG, the judgement was classified as undiagnosed. The patients were divided into two groups according to the unavoidable use of NTG: U-NTG (n = 42) and the final use of NTG: F-NTG (n = 99). The clinical characteristics and frequencies of MVS (≥2 major coronary arteries in which a coronary spasm was provoked) and complications (malignant arrhythmia and unstable haemodynamics requiring catecholamines) during the SPT were compared between the groups. Results: Except for smoking status, all other clinical characteristics did not differ significantly between the groups. More current smokers were observed in the U-NTG group (29%) than in the F-NTG group (12%, p = 0.02). The frequency of MVS did not vary significantly between the groups (p = 0.28), with 64% for U-NTG and 55% for F-NTG. No significant difference was found between the groups in the frequency of severe complications during SPT (p = 0.83), with 2% for U-NTG and 3% for F-NTG. In the U-NTG group, the positive induction rate of coronary spasm in another coronary artery was 40% (17/42). Conclusions: The unavoidable use of NTG occurred in ~30% of patients with VSA, most of whom were current smokers. It did not decrease the detection of MVS and potentially prevented severe complications during SPT. Therefore, the unavoidable use of NTG is acceptable during SPT. However, an additional test may need to be performed to assess the presence of MVS.

Does the intracoronary pressure differ according to two types (diffuse or focal) of coronary spasm?

BACKGROUND: Several reports show that two types of coronary vasospasm (diffuse and focal spasm) are associated with the severity or prognosis of coronary spasm in patients with vasospastic angina (VSA). It is unclear whether intracoronary pressure differs between the two spasm types. AIM: To investigate such relationships using a pressure wire during the spasm provocation test (SPT) in patients with VSA. METHODS: Eighty-seven patients with VSA (average age: 67 years; 50 men, 37 women) underwent SPT. During the SPT, a pressure wire was advanced into the distal portion of the right coronary artery and left anterior descending coronary artery, and the ratio of the intracoronary pressure to the aortic pressure (Pd/Pa) was continuously monitored. An SPT was performed using acetylcholine (ACh), and the presence of coronary spasm was defined as the presence of > 90% arterial narrowing in response to an ACh infusion, with the usual chest symptoms and/or ischemic ECG changes. Focal spasm was defined as total or subtotal spasm within one segment of the AHA classification, while diffuse spasm was defined as > 90% spasm with two or more segments. RESULTS: Among 87 patients, the frequencies of metabolic syndrome and having coronary atherosclerosis were higher in the focal group (n = 33) than in the diffuse spasm group (n = 54, P < 0.05). In the vessel analyses, in these 134 spastic segments, diffuse and focal spasms were detected in 100 and 34 vessels, respectively. The Pd/Pa at baseline was similar in both groups (diffuse: 0.96 ± 0.05, focal: 0.95 ± 0.05, P = 0.35); however, the Pd/Pa during coronary spasm was lower in focal spastic vessels (0.66 ± 0.20) than in diffuse spastic vessels (0.76 ± 0.11, P < 0.01), and the reduction in Pd/Pa during an SPT was also lower in focal spastic vessels (-0.29 ± 0.20) than in diffuse spastic vessels (-0.18 ± 0.11, P < 0.01). The presence of focal spasm was a significant factor responsible for reduction in Pd/Pa during SPT. CONCLUSION: These findings suggest that focal spasm may be more severe than diffuse spasm, judging from the intracoronary pressure during coronary spasm.

Japanese Herbal Medicine (Kampo) as a Possible Treatment for Ischemia With Non-obstructive Coronary Artery Disease.

Patients presenting with the syndrome of symptoms and signs suggesting ischemic heart disease but found to have no obstructed coronary arteries (INOCA) are increasingly recognized. Although there are non-invasive tests for the diagnosis of INOCA, such as transthoracic Doppler echocardiography, positron emission tomography, and cardiac magnetic resonance imaging to evaluate increased blood flow with adenosine and other agents, the diagnosis of INOCA by coronary angiography with the coronary spasm provocation test and coronary microvascular function evaluation using pressure wires has become the gold standard, but it is not well established in the treatment of INOCA. Despite the lack of objection to lifestyle modification and the use of coronary dilators, mainly calcium-channel blockers, for conditions involving epicardial coronary artery spasm, there is no entirely effective long-term treatment for microvascular spasm or coronary microvascular dysfunction. Although some combinations of drugs have been empirically administered in certain cases, it is difficult to conclude that they are sufficiently effective. Recently, it has been reported that some Japanese herbal medicines (Kampo) have been effective in the treatment of INOCA. In order to increase the knowledge on the treatment of INOCA, this review focuses on the effects of Japanese herbal medicine on INOCA and its presumed mechanisms and problems.