Mineralocorticoid Receptor Blocker Prevents Mineralocorticoid Receptor-Mediated Inflammation by Modulating Transcriptional Activity of Mineralocorticoid Receptor-p65-Signal Transducer and Activator of Transcription 3 Complex.

BACKGROUND: Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor-κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti-inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti-inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms. METHODS AND RESULTS: Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanized at either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory-related gene expression, and elevated serum interleukin-6 levels at 4 days after MI were significantly attenuated by esaxerenone. In vitro experiments using mouse macrophage-like cell line RAW264.7 cells demonstrated that esaxerenone- and spironolactone-attenuated lipopolysaccharide-induced interleukin-6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65-STAT3 interaction, leading to a subsequent increase in interleukin-6 promoter activity, which was reversed by esaxerenone. CONCLUSIONS: Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti-inflammatory properties exerted by modulating the transcriptional activity of the MR-p65-STAT3 complex. These results suggest that the MR-p65-STAT3 complex can be a novel therapeutic target for treating MI.

Pharmacological and Device-Based Intervention for Preventing Heart Failure After Acute Myocardial Infarction　- A Clinical Review.

In patients with acute myocardial infarction (MI), heart failure (HF) is one of the most common complications that is associated with a significant burden of mortality and healthcare resources. The clinical benefits of key HF drugs, the so-called "4 pillars" or "fantastic 4", namely ß-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitor, and sodium-glucose cotransporter 2 inhibitors, have been established in patients with HF with reduced ejection fraction, whereas the effects of these drugs are not comprehensively appreciated in patients with acute MI. This review summarizes current evidence on pharmacological and device-based interventions for preventing HF after acute MI.

Corrigendum to "Impact of heart failure severity and major bleeding events after percutaneous coronary intervention on subsequent major adverse cardiac events" [Int. J. Cardiol. Cardiovasc. Risk and Prev. 2023 Jun 25:18:200193].

[This corrects the article DOI: 10.1016/j.ijcrp.2023.200193.].

Change in pulse pressure and cardiovascular outcomes after percutaneous coronary intervention: The CLIDAS study.

Background: Limited data exist on the prognostic value of changes in pulse pressure (PP, the difference between systolic and diastolic blood pressure) during hospitalization for patients with coronary artery disease who have undergone percutaneous coronary intervention (PCI). Methods: In the Clinical Deep Data Accumulation System (CLIDAS), we studied 8,708 patients who underwent PCI. We aimed to examine the association between discharge PP and cardiovascular outcomes. PP was measured before PCI and at discharge. Patients were divided into five groups (quintiles) based on the change in PPQ1 (-18.0 ± 9.9 mmHg), Q2 (-3.8 ± 2.6), Q3 (reference; 3.7 ± 2.0), Q4 (11.3 ± 2.6), and Q5 (27.5 ± 11.2). We then analyzed the relationship between PP change and outcomes. Results: The mean patient age was 70 ± 11 years, with 6,851 (78 %) men and 3,786 (43 %) having acute coronary syndrome. U-shaped relationships were observed for the incidence rates of major adverse cardiac or cerebrovascular events (MACCE, a composite endpoint of cardiovascular death, myocardial infarction, and stroke), revascularization, and hospitalization for heart failure (HF). After adjusting for confounding factors, higher PP at discharge was associated with an increased risk of MACCE (adjusted hazard ratio 1.41; 95 %CI, 1.06-1.87 in Q5 [73.9 ± 9.3 mmHg]). Evaluating PP change revealed a U-shaped association with MACCE (1.50; 1.11-2.02 in Q1 and 1.47; 0.98-2.20 in Q5). Additionally, Q5 had a higher risk for hospitalization for HF (1.37; 1.00-1.88). Conclusions: Our findings demonstrate a U-shaped association between changes in PP and cardiovascular outcomes. This data suggests the significance of blood pressure control during hospitalization for patients who have undergone PCI.

Transthyretin amyloid cardiomyopathy: Literature review and red-flag symptom clusters for each cardiology specialty.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is a progressive and infiltrative cardiac disorder that may cause fatal consequences if left untreated. The estimated survival time from diagnosis is approximately 3-6 years. Because of the non-specificity of initial symptom manifestation and insufficient awareness among treating physicians, approximately one-third of patients with ATTRwt-CM are initially misdiagnosed with other cardiac diseases. Although heart failure (HF) is the most common initial manifestation of ATTRwt-CM, observed in nearly 70% of affected patients, patients may also present with other cardiologic symptoms, such as atrial fibrillation (AF) and aortic stenosis (AS). This non-specific and diverse nature of the initial ATTRwt-CM presentation indicates that various cardiology subspecialties are involved in patient diagnosis and management. Standard guideline-directed pharmacological treatment for HF is not recommended for patients with ATTRwt-CM because of its limited effectiveness. However, no established algorithms are available regarding HF management in this patient population. This literature review provides an overview of the red flags for ATTRwt-CM and research findings regarding HF management in this patient population. In addition to commonly recognized red flags for ATTRwt-CM (e.g., HF, AF and severe AS), published literature identified potential red flags such as coronary microvascular dysfunction. For HF management in patients with ATTRwt-CM, the use of mineralocorticoid receptor antagonists (MRAs) was reported as a well-tolerated option associated with a low discontinuation rate and reduced mortality. Although there is no concrete evidence for recommendations against sodium-glucose cotransporter 2 inhibitor (SGLT2i) administration, research supporting its use is limited to small-scale studies. Robust evidence is lacking for AF ablation, implantable cardioverter-defibrillators and cardiac resynchronization therapy. Based on the published findings and our clinical experience as Japanese ATTRwt-CM experts, red-flag symptom clusters for each cardiology specialty (HF, arrhythmia and ischaemia/structural heart disease) and a treatment scheme for HF management are presented. As this research area remains at an exploratory stage, our observations would require further discussion among experts worldwide.

Long-Term Impact of the Kumamoto Earthquake on Out-of-Hospital Cardiac Arrest With Cardiac and Non-Cardiac Origins　- An Interrupted Time Series Analysis.

BACKGROUND: Possible etiologies of out-of-hospital cardiac arrest (OHCA), including aortic dissection, ruptured aortic aneurysms, and pulmonary embolism, may be classified as non-cardiac causes. We investigated whether cardiac and non-cardiac OHCAs increased following the Kumamoto earthquake and whether the impact on OHCAs extended to regions far from the epicenter. METHODS AND RESULTS: We prospectively analyzed a nationwide registry of patients who experienced OHCAs between January 2013 and December 2019. Data from cases registered in 7 prefectures, including Kumamoto (Kyushu region; n=82,060), in the All-Japan Utstein Registry were analyzed for OHCAs of cardiac and non-cardiac origin. The numbers of OHCAs before and after the Kumamoto earthquake were compared using an interrupted time series analysis. The incidence of both cardiac (rate ratio [RR] 1.22) and non-cardiac (RR 1.27) OHCAs in Kumamoto Prefecture increased after the earthquake. The difference disappeared when the analysis was limited to patients with non-cardiac OHCAs with a clear cause of cardiac arrest. The number of cardiac and non-cardiac OHCAs did not increase in other prefectures within the Kyushu region. CONCLUSIONS: The Kumamoto earthquake led to an increase in the incidence of cardiac and non-cardiac OHCAs. However, this was attenuated by increasing distance from the epicenter. Except for cardiac causes, cases complicated by earthquake-related events may include non-cardiac OHCAs due to vascular diseases that might be overlooked.

Factors influencing the efficacy and safety of esaxerenone in hypertensive patients: a pooled analysis of five clinical studies on different comorbidities.

This study aimed to identify factors associated with a strong home blood pressure (BP)-lowering effect of esaxerenone and the incidence of elevated serum potassium levels in hypertensive patients treated with esaxerenone. A pooled analysis of five multicenter, prospective, open-label single-arm studies was conducted, including 479 patients in the full analysis set (FAS) and 492 patients in the safety analysis set. Multivariate linear regression analysis of morning home systolic BP (SBP) and diastolic BP (DBP) changes from baseline to Week 12 in the FAS (primary endpoint) showed that male sex (estimated change 4.37 mmHg), office pulse rate ≥100 beats/min (25.10 mmHg), and calcium channel blocker (CCB) use as a basal antihypertensive agent (4.53 mmHg) were significantly associated with a positive estimated change (weaker BP-lowering effect) in morning home SBP. CCB use (3.70 mmHg) was associated with a positive estimated change in morning home DBP. Urine albumin-to-creatinine ratio 30 to <300 mg/gCr (-4.13 mmHg) was significantly associated with a negative estimated change (stronger BP-lowering effect) in morning home SBP. Based on multivariate logistic regression analysis, elevated baseline serum potassium level (≥4.5 vs < 4.5 mEq/L, odds ratio 13.502) was significantly associated with a high incidence of serum potassium level ≥5.5 mEq/L after esaxerenone treatment. In conclusion, factors associated with a strong BP-lowering effect of esaxerenone were female sex and use of renin-angiotensin system inhibitors as a basal antihypertensive drug. Patients with baseline serum potassium levels ≥4.5 mEq/L had an increased risk of developing elevated serum potassium levels (≥5.5 mEq/L) after esaxerenone treatment.

Impact of Antiplatelet Therapy on 5-Year Outcomes After Fractional Flow Reserve-Guided Deferral of Revascularization in Nonsignificant Obstructive Coronary Artery Disease.

Background: Because the clinical benefit of antiplatelet therapy (APT) for patients with nonsignificant coronary artery disease (CAD) remains poorly understood, we evaluated it in patients after fractional flow reserve (FFR)-guided deferral of revascularization. Methods and Results: From the J-CONFIRM (Long-Term Outcomes of Japanese Patients with Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), we investigated 265 patients with deferred lesions who did not require APT for secondary prevention of cardiovascular disease. A 2-year landmark analysis assessed the relationship between APT at 2 years and 5-year major cardiac adverse events (MACE: composite of all-cause death, target vessel-related myocardial infarction, clinically driven target vessel revascularization). Of the 265 patients, 163 (61.5%) received APT. The 5-year MACE did not significantly differ between the APT and non-APT groups after adjustment for baseline clinical characteristics (9.2% vs. 6.9%, inverse probability weighted hazard ratio, 1.40 [95% confidence interval, 0.53-3.69]; P=0.49). There was a marginal interaction between the effect of APT on MACE and FFR values (< or ≥0.84) (P for interaction=0.066). Conclusions: The 5-year outcomes after FFR-guided deferral of revascularization did not significantly differ between the APT and non-APT groups, suggesting that APT might not be a critical requirement for nonsignificant obstructive CAD patients not requiring APT for secondary prevention of cardiovascular disease.

R2-CHA2DS2-VASc Score for Cardiovascular Event Prediction After Bioprosthetic Valve Replacement　- Subanalysis From the BPV-AF Registry.

Background: There are few studies evaluating the prognostic prediction method in atrial fibrillation (AF) patients after bioprosthetic valve (BPV) replacement. The R2-CHA2DS2-VASc score is increasingly used for the prediction of cardiovascular (CV) events in patients with AF, device implantation, and acute coronary syndrome. We aimed to evaluate the predictive value of the R2-CHA2DS2-VASc score for future CV events in AF patients after BPV replacement. Methods and Results: The BPV-AF, an observational, multicenter, prospective registry, enrolled AF patients who underwent BPV replacement. The primary outcome measure was a composite of stroke, systemic embolism, CV events including heart failure requiring hospitalization, and cardiac death. A total of 766 patients was included in the analysis. The mean R2-CHA2DS2-VASc score was 5.7±1.8. Low (scores 0-1), moderate (scores 2-4), and high (scores 5-11) R2-CHA2DS2-VASc score groups consisted of 12 (1.6%), 178 (23.2%), and 576 (75.2%) patients, respectively. The median follow-up period was 491 (interquartile range 393-561) days. Kaplan-Meier analysis showed a higher incidence of the composite CV events in the high R2-CHA2DS2-VASc score group (log rank test; P<0.001). Multivariate Cox proportional hazards regression analysis revealed that the R2-CHA2DS2-VASc score as a continuous variable was an independent predictor of composite CV outcomes (hazard ratio 1.36; 95% confidence interval 1.18-1.55; P<0.001). Conclusions: The R2-CHA2DS2-VASc score is useful for CV risk stratification in AF patients after BPV replacement.

Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically. RESULTS: A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). A primary end-point event occurred in 163 patients in the vutrisiran group and in 202 in the placebo group. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group. CONCLUSIONS: Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.).

Clinical Comparison of Drug-Coated Balloon and Drug-Eluting Stent for Femoropopliteal Lesions in Chronic Limb-Threatening Ischemia With Wounds.

BACKGROUND: Endovascular therapy (EVT) with devices such as drug-coated balloons (DCBs) and drug-eluting stents (DESs) for atherosclerotic disease in the femoropopliteal (FP) artery has been established. However, EVT using drug-based devices for chronic limb-threatening ischemia (CLTI) remains challenging. The optimal device for FP lesions in patients with CLTI remains unknown. This study compared the clinical efficacy of DCB and DES in patients with CLTI and FP lesions.Methods and Results: This retrospective single-center study included 539 consecutive patients (562 lesions) treated with EVT between January 2018 and December 2022; 166 patients with CLTI and Rutherford Class 5 or 6 wounds underwent EVT with DCB or DES. Clinical outcomes were compared between 53 pairs after propensity score matching. There were no significant differences between the DCB and DES groups in the incidence of complete wound healing without death or major amputation (84.8% vs. 80.2%, respectively; P=0.99), primary patency (69.4% vs. 75.6%, respectively; P=0.65), and freedom from target lesion revascularization at 1 year (78.6% vs. 78.0%, respectively; P=0.92). Multivariate analysis showed that complete wound healing at 1 year is negatively associated with hemodialysis and Wound, Ischemia, and foot Infection Stage 4, but positively associated with Global Limb Anatomic Staging System FP Grade 3 or 4. CONCLUSIONS: No significant differences in clinical outcomes were found between DCB and DES for patients with CLTI and FP lesions.

State-of-the-art percutaneous coronary intervention for left main coronary artery disease in Japan.

Percutaneous coronary intervention for left main coronary artery disease (LM-PCI) represents a high-risk yet life-saving procedure that has evolved significantly over the years. This review outlines the current state-of-the-art practices for LM-PCI in Japan in detail, emphasizing the integration of coronary physiology and intracoronary imaging alongside with evidence-based standardized technique using latest drug-eluting stents. These advancements enable precise lesion assessment, stent sizing, and optimal deployment, thereby enhancing procedural safety and efficacy. Despite discrepancies between current guidelines favoring coronary artery bypass grafting and real-world practice trends towards increased LM-PCI adoption, particularly in elderly populations with multiple comorbidities, careful patient selection and procedural planning are critical. Future perspectives include further refining LM-PCI through conducting randomized controlled trials integrating advanced techniques and addressing the issue of ostial left circumflex lesions and nationwide standardization of medical care for LM disease.

Clinical effects of direct oral anticoagulants in elderly patients with a bioprosthetic valve and atrial fibrillation.

BACKGROUND: Current guidelines recommend direct oral anticoagulants (DOACs) and warfarin for patients with atrial fibrillation (AF) who have a bioprosthetic valve (BPV). However, the data related to elderly patients (aged ≥80 years) with BPV replacement and AF are limited. METHODS: This post-hoc subgroup analysis of a BPV-AF Registry enrolled 752 patients with BPV replacement and AF. The primary net outcome was a composite of cardiac death, stroke, systemic embolism, major bleeding, and cardiovascular events. RESULTS: Among 752 patients, 429 (57%) patients were ≥ 80 and 323 (43%) were < 80 years old. The higher risk in patients aged ≥80 than <80 years was significant for the net outcome (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.31-3.17; P = 0.001). After adjustment for confounders, there was no statistically significant difference between warfarin (reference) and DOAC users in the risk of net outcomes (adjusted HR, 1.26; 95% CI, 0.71-2.24; P = 0.44), stroke and systemic embolism (adjusted HR, 2.01; 95% CI, 0.48-8.38; P = 0.34), and major bleeding (adjusted HR, 0.73; 95% CI, 0.11-4.98; P = 0.75) in patients aged ≥80 years old as well as those aged <80 years. Among 489 warfarin users, the cumulative incidence of net outcomes tended to be higher in patients aged ≥80 than <80 years (12.2% vs. 5.7% at 1 year, log-rank P = 0.002). Among 263 DOAC users, however, it was similar between patients aged ≥80 and < 80 years. CONCLUSIONS: The present study demonstrated that DOAC showed similar efficacy and safety compared with warfarin even in elderly patients aged ≥80 years with BPV replacement and AF.