Comparison of incident hypertension between SGLT2 inhibitors vs. DPP4 inhibitors.

Although several randomized clinical trials have reported the potential benefit of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in reducing blood pressure (BP), whether SGLT2i can reduce incident hypertension is unknown. We analyzed individuals with diabetes who were newly prescribed SGLT2i or dipeptidyl peptidase 4 inhibitors (DPP4i) in a large-scale epidemiological database. The primary outcome was the incidence of hypertension. A propensity score matching algorithm was employed to compare the subsequent development of hypertension between the SGLT2i and DPP4i groups. After propensity score matching, 5708 well-balanced pairs of SGLT2i and DPP4i users were identified. SGLT2i administration was associated with a reduced risk of hypertension (HR 0.91, 95% CI: 0.84-0.97). The advantage of SGLT2i use over DPP4i use for incident hypertension was generally consistent in several sensitivity analyses, and subgroup analyses showed that SGLT2i use was significantly associated with a lower risk of hypertension in men, patients with baseline HbA1c of <7.5%, and baseline systolic blood pressure ≥127 mmHg. Our investigation using nationwide real-world data demonstrated the potential advantage of SGLT2i over DPP4i in reducing the development of hypertension in individuals with diabetes.

Unawareness of being prescribed medications for diabetes and incident cardiovascular disease.

BACKGROUND: Some patients with diabetes are unaware that they are prescribed medications for diabetes. The purpose of this study is to determine, using a Japanese nationwide epidemiologic database, the association between unawareness of being prescribed medication for diabetes and the risk of developing cardiovascular disease (CVD) in patients with diabetes. METHODS: This observational cohort study analyzed data from the JMDC Claims Database between 2005 and 2022, including 94,048 patients with diabetes treated with medications. The primary endpoint was a composite endpoint including myocardial infarction (MI), stroke, heart failure (HF), and atrial fibrillation (AF). RESULTS: We identified 7561 composite CVD endpoints during a mean follow-up of 1199 ±â€¯902 days. Overall, 7779 (8.3 %) patients were unaware of being prescribed medications for diabetes. Those who did not know they were prescribed drugs were younger and had better glycemic control, but these individuals were at higher risk of developing combined CVD [hazard ratio (HR) 1.13, 95 % confidence interval (95 % CI) 1.04-1.22]. HRs of unawareness of being prescribed medications for diabetes were 1.33 (95 % CI 1.06-1.68) for MI, 1.13 (95 % CI 0.97-1.31) for stroke, 1.10 (95 % CI 1.00-1.21) for HF, and 1.19 (95 % CI 0.97-1.47) for AF, respectively. CONCLUSIONS: In patients with diabetes taking medications for diabetes, even if they are young and have good glycemic control, unawareness of being prescribed medications for diabetes was associated with a greater risk of developing CVD. It is important that they receive adequate education from their healthcare providers to accurately identify their treatment status.

Impact of cancer in patients with aortic stenosis undergoing transcatheter aortic valve replacement: A systematic review and meta-analysis.

Background: Owing to the minimally invasive nature of transcatheter aortic valve replacement (TAVR), TAVR seems to be preferred in patients with cancer; however, related research on the clinical efficacy and safety of TAVR in patients with cancer and severe aortic stenosis is limited, and conclusions are controversial. This study aimed to evaluate the clinical outcomes of patients with cancer who underwent TAVR. Method and results: We conducted a systematic review and meta-analysis to investigate the clinical outcomes in patients with and without cancer who underwent TAVR. We systematically reviewed and analyzed 15 studies (195,658 patients) published in PubMed and Cochrane Library databases between January 2022 and January 2023. The primary outcomes were short-term (in-hospital or 30-day) and long-term (≥12 months) mortality. The prevalence of current or previous cancer in the patients undergoing TAVR was 19.8 % (38,695 patients). Patients with cancer had a lower risk of short-term mortality (odds ratio [OR] 0.69, 95 % confidence interval [CI] 0.61-0.77, P < 0.001) but a higher risk of long-term mortality (OR 1.54, 95 % CI 1.35-1.76, P < 0.001) than those without cancer. Patients with cancer had a lower incidence of postprocedural stroke and acute kidney injury but a higher incidence of pacemaker implantation than patients without cancer. Conclusions: Patients with cancer undergoing TAVR have a good short-term prognosis and acceptable perioperative complications compared with patients without cancer. However, the long-term outcomes are contingent on cancer survival.

An inherited life-threatening arrhythmia model established by screening randomly mutagenized mice.

Inherited arrhythmia syndromes (IASs) can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden cardiac deaths (SCDs). Despite progress in the development of devices to prevent SCDs, the precise molecular mechanisms that induce detrimental arrhythmias remain to be fully investigated, and more effective therapies are desirable. In the present study, we screened a large-scale randomly mutagenized mouse library by electrocardiography to establish a disease model of IASs and consequently found one pedigree that exhibited spontaneous ventricular arrhythmias (VAs) followed by SCD within 1 y after birth. Genetic analysis successfully revealed a missense mutation (p.I4093V) of the ryanodine receptor 2 gene to be a cause of the arrhythmia. We found an age-related increase in arrhythmia frequency accompanied by cardiomegaly and decreased ventricular contractility in the Ryr2I4093V/+ mice. Ca2+ signaling analysis and a ryanodine binding assay indicated that the mutant ryanodine receptor 2 had a gain-of-function phenotype and enhanced Ca2+ sensitivity. Using this model, we detected the significant suppression of VA following flecainide or dantrolene treatment. Collectively, we established an inherited life-threatening arrhythmia mouse model from an electrocardiogram-based screen of randomly mutagenized mice. The present IAS model may prove feasible for use in investigating the mechanisms of SCD and assessing therapies.

Predictors and Incidence of Health Status Deterioration in Patients with Early Atrial Fibrillation.

BACKGROUND: Various treatment approaches for atrial fibrillation (AF) have demonstrated improved health status, yet the significance of these therapeutic interventions in individual patients remains unclear. OBJECTIVE: This study aimed to evaluate health status changes in patients with early AF, focusing on those who experience clinically significant deterioration following treatment initiation. METHODS: We analyzed data from a multicenter, prospective registry of newly diagnosed patients with AF. One-year changes in health status across different treatment strategies were assessed using the Atrial Fibrillation Effect on QualiTy-of-life Overall Summary (AFEQT-OS) score. Clinically relevant deterioration and improvement in health status were defined as ≥5-point decrease and increase in AFEQT-OS score, respectively; no change was -5 to 5 points. RESULTS: Overall, 1,960 patients with AF were evaluated. Mean AFEQT-OS score at baseline and 1-year follow-up were 76.7±17.7 and 85.4±14.8, respectively. Although most patients (53.9%) experienced clinically important improvement, a considerable proportion had no change (28.7%) or deterioration (17.4%) in their health status. Proportions of patients with no change or deterioration varied by treatment strategy: 59.9, 53.9, and 32.0% in rate control, antiarrhythmic drug, and catheter ablation groups, respectively. Multivariable model identified older age, female sex, heart failure, coronary artery disease, and higher baseline AFEQT-OS score as independent predictors of worsening health status, regardless of treatment strategy. CONCLUSION: Many patients with early AF experience worsening or no change in health status irrespective of treatment strategy. Standardizing patients' health status assessment, especially for patients with comorbidities may aid in patients' selection and their outcomes.

Coronary Artery Bypass Grafting for a Young Female Patient With Chronic Active Epstein-Barr Virus Infection.

A 24-year-old woman with chronic active Epstein-Barr virus (CAEBV) infection successfully underwent coronary artery bypass grafting for triple coronary arteries with chronic total occlusion and aneurysms. This case underscores the importance of accurate assessment and treatment of coronary artery lesions in patients with CAEBV infection.

Assessment of patient characteristics influencing the complexity of leadless pacemaker implantation.

Background: The complexity of leadless pacemaker (LP) implantation varies widely. However, the predictive factors determining this difficulty are poorly understood. Objective: The purpose of this study was to evaluate the factors influencing LP implantation difficulty, specifically procedural time during right atrial (RA) and right ventricular (RV) manipulation, based on patient background, cardiac function, and anatomic characteristics. Methods: Analysis included LP implantation cases between 2017 and 2023, excluding the initial 3 implants performed by each operator. The relevance of patient background, cardiac function, and anatomic features on procedural and fluoroscopy times was evaluated. Results: Fifty-four patients (mean age 82.2 ± 10.0 years; 57.4% male) were included in the study. Median procedural and fluoroscopy time was 45.8 minutes and 16.0 minutes, respectively, with an average of 2.0 ± 1.4 device deployments. Univariate analysis showed associations between procedural time and older age, RA and RV diameter, and severity of tricuspid regurgitation (TR). After adjustment for physician and potential contributing factors, RV dilation (midventricular diameter ≥35 mm) and severe TR were identified as independent predictors of prolonged procedural time. Medical history exhibited no association with procedural time. Consistent results were observed in analyses using fluoroscopy time as the outcome. Conclusion: RV dilation and severe TR were associated with prolonged procedural time for LP implantation. Anatomic features obtained from preprocedural echocardiography could provide valuable insights into both the safety and efficiency of LP implantation, thereby enhancing tailored treatment strategies for patients undergoing pacemaker implantation.

Immediate pharmacotherapy intensification after cardiac resynchronization therapy: incidence, characteristics, and impact.

AIMS: Cardiac resynchronization therapy (CRT) is an established treatment for drug-refractory heart failure (HF) in patients with left bundle branch block (LBBB). Acute haemodynamic improvement after CRT implantation may enable the intensification of HF medication soon thereafter. Immediate pharmacotherapy intensification (IPI) after CRT implantation achieves a synergetic effect, possibly leading to a better prognosis. This study aimed to explore the incidence, characteristics, and impact of IPI on real-world outcomes among CRT recipients with a history of hospitalization for acute HF. METHODS AND RESULTS: This multicentre retrospective study enrolled CRT recipients with LBBB morphology, a QRS width ≥120 ms, a left ventricular ejection fraction ≤35%, and New York Heart Association II-IV HF symptoms. All patients had previous HF hospitalizations within the previous year and received guideline-directed medical therapy before CRT implantation. Patient baseline characteristics, including HF medication, were collected. IPI was defined as the intensification of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists within 30 days of CRT implantation. The primary endpoint was all-cause death or first hospitalization for HF; the secondary endpoint was all-cause death. We enrolled 194 patients (75% male; mean age, 65 ± 13 years; 78% with non-ischaemic cardiomyopathy). One hundred five (54%) patients received IPI. Patients who received IPI exhibited a significantly shorter QRS duration (159 ± 26 vs. 171 ± 32 ms; P = 0.004), higher estimated glomerular filtration rate (55.2 ± 20.0 vs. 47.8 ± 24.7 mL/min/1.73 m2 ; P = 0.022), and more dilated cardiomyopathy. During a median follow-up period of 29 months, 70 (36%) patients reached the primary endpoint and 42 (22%) patients died. Patients with IPI showed significantly better outcomes for the primary and secondary endpoints than patients without IPI. The volumetric responder ratio at 6 months after implantation was not significantly different between patients with and without IPI; however, patients who received IPI had reduced mortality even at 6 months after implantation. In the multivariate analysis, IPI was an independent predictor of the primary endpoint (hazard ratio, 0.51; 95% confidence interval, 0.27-0.97; P = 0.043). CONCLUSIONS: Immediate intensification of HF medication was achieved in 54% of CRT recipients and was significantly higher in patients without excessive QRS prolongation, preserved renal function, and dilated cardiomyopathy than others. In patients with LBBB morphology and QRS ≥ 120 ms, IPI was associated with a significantly better prognosis and fewer HF hospitalizations after CRT implantation than others.

Sex Differences in the Relationship Between Schizophrenia and the Development of Cardiovascular Disease.

BACKGROUND: There are few data on sex differences in the association between schizophrenia and the development of cardiovascular disease (CVD). We sought to clarify the relationship of schizophrenia with the risk of developing CVDs and to explore the potential modification effect of sex differences. METHODS AND RESULTS: We conducted a retrospective analysis using the JMDC Claims Database between 2005 and 2022. The study population included 4 124 508 individuals aged 18 to 75 years without a history of CVD or renal replacement therapy. The primary end point is defined as a composite end point that includes myocardial infarction, angina pectoris, stroke, heart failure, atrial fibrillation, and pulmonary thromboembolism. During a mean follow-up of 1288±1001 days, we observed 182 158 composite end points. We found a significant relationship of schizophrenia with a greater risk of developing composite CVD events in both men and women, with a stronger association observed in women. The hazard ratio for the composite end point was 1.63 (95% CI, 1.52-1.74) in women and 1.42 (95% CI, 1.33-1.52) in men after multivariable adjustment (P for interaction=0.0049). This sex-specific difference in the association between schizophrenia and incident CVD was consistent for angina pectoris, heart failure, and atrial fibrillation. CONCLUSIONS: Our analysis using a large-scale epidemiologic cohort demonstrated that the association between schizophrenia and subsequent CVD events was more pronounced in women than in men, suggesting the clinical importance of addressing schizophrenia and tailoring the CVD prevention strategy based on sex-specific factors.

Physician Estimates and Patient-Reported Health Status in Atrial Fibrillation.

Importance: A primary objective in managing atrial fibrillation (AF) is to optimize patients' health status, which can be done only if physicians accurately quantify the outcomes associated with AF in patients' lives. Objective: To explore physicians' estimation of the health status of patients with AF and its association with subsequent care and outcomes. Design, Setting, and Participants: A multicenter, prospective cohort study was conducted in 2 outpatient practices in Tokyo, Japan. Participants included patients with newly diagnosed AF or those referred for initial treatment of AF at outpatient practices and treating physicians from November 8, 2018, to April 1, 2020. Data analysis was performed from December 22, 2022, to July 7, 2023. Exposures: Participating patients completed the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire, a 20-item tool covering 4 domains with a 7-point Likert scale; 3 domains (symptoms, daily activities, and treatment concerns) were used in this study. Blinded to patients' responses, treating physicians answered a 3-item questionnaire quantifying each patient's AFEQT domain with a single item. Patients' mean Likert scale responses within each AFEQT domain were subtracted from the physicians' assessments so that higher scores (≥0.5 points) indicate physician underestimation, while lower scores (≤0.5 points) indicate physician overestimation of the health status of patients with AF. Main Outcomes and Measures: The independent association of physician-patient concordance with treatment escalation (alteration or initiation of antiarrhythmic drugs, cardioversion, or catheter ablation) and 1-year adjusted changes in AFEQT scores. Results: Among 330 patients (238 [72.1%] men; mean [SD] age, 67.9 [11.9] years; 163 [49.4%] with paroxysmal AF), physicians correctly estimated health status in 112 patients (33.9%), underestimated it in 42 patients (12.7%), and overestimated it in 176 patients (53.3%). Treatment escalation occurred in 63.6% of patients whose health status was correctly estimated, 47.6% of those whose health status was underestimated, and 66.3% of patients whose health status was overestimated. After multivariable adjustment, underestimation of health status was independently associated with less treatment escalation (adjusted odds ratio, 0.43; 95% CI, 0.20-0.90) and less frequent AFEQT overall summary score improvement at 1 year (underestimated, 2.5 [95% CI, -1.6 to 6.7] vs correctly and overestimated health status, 8.4 [95% CI, 7.0-9.9] points; P = .01). Conclusions and Relevance: In this cohort study, physician underestimation of the health status of patients with AF was common and associated with less aggressive treatment and less health status improvement at 1 year.

Clinical Utility of Baseline Brain Natriuretic Peptide Levels on Health Status Outcomes after Catheter Ablation for Atrial Fibrillation in Individuals without Heart Failure.

BACKGROUND: Catheter ablation (CA) benefits atrial fibrillation (AF) patients with heart failure (HF). Brain natriuretic peptide (BNP), a marker of left-ventricular pressure load, may serve as a potential surrogate for predicting quality of life (QOL) in a broader range of patients. METHODS: Within the multicenter KiCS-AF registry, 491 AF patients underwent CA without clinical HF (e.g., documented history of HF, left ventricular ejection fraction ≤ 40%, or BNP levels ≥ 100 pg/mL). Participants, aged 61 ± 10 years, were categorized by baseline BNP quartiles. Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) questionnaire assessments were assessed at baseline and 1 year. RESULTS: A lower baseline BNP correlated with reduced AFEQT scores. Post CA, all groups showed significant AFEQT score improvements. The lower-BNP group displayed notable enhancements (18.2 ± 1.2, 15.0 ± 1.1, 12.6 ± 1.2, 13.6 ± 1.2, p < 0.005), especially in symptom and treatment concern areas. Even those with normal BNP levels (≤18.4 pg/mL) exhibited significant QOL improvements. Comparing paroxysmal AF (PAF) and non-PAF groups, the PAF group, especially with higher BNP levels, showed greater AFEQT score improvements. CONCLUSIONS: This study establishes BNP as a predictive marker for QOL enhancement in non-HF patients undergoing CA for AF. BNP levels represent AF stages, with individuals in earlier stages, especially within normal BNP levels, experiencing greater QOL improvements.

Successful Treatment of Malignant Lymphoma Following Transcatheter Aortic Valve Replacement: A Case Report.

A 67-year-old woman with severe aortic stenosis (AS) was transferred to our hospital for large B-cell lymphoma treatment. Because of her high risk of anthracycline-induced cardiotoxicity due to severe AS and low performance status, the patient was initially treated with doxorubicin-free chemotherapy. However, doxorubicin was considered necessary to achieve complete remission. After multidisciplinary team discussions, transcatheter aortic valve replacement (TAVR) was performed without complications. Nine days after TAVR, the patient received the first cycle of anthracycline-containing chemotherapy (R-CHOP). Currently, 12 months after completing 4 cycles of R-CHOP, the patient remains in complete remission without having developed cardiotoxicity.

Cardiac reprogramming reduces inflammatory macrophages and improves cardiac function in chronic myocardial infarction.

Cardiomyocytes (CMs) have little regenerative capacity. After myocardial infarction (MI), scar formation and myocardial remodeling proceed in the infarct and non-infarct areas, respectively, leading to heart failure (HF). Prolonged activation of cardiac fibroblasts (CFs) and inflammatory cells may contribute to this process; however, therapies targeting these cell types remain lacking. Cardiac reprogramming converts CFs into induced CMs, reduces fibrosis, and improves cardiac function in chronic MI through the overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH). However, whether cardiac reprogramming reduces inflammation in infarcted hearts remains unclear. Moreover, the mechanism through which MGTH overexpression in CFs affects inflammatory cells remains unknown. Here, we showed that inflammation persists in the myocardium until three months after MI, which can be reversed with cardiac reprogramming. Single-cell RNA sequencing demonstrated that CFs expressed pro-inflammatory genes and exhibited strong intercellular communication with inflammatory cells, including macrophages, in chronic MI. Cardiac reprogramming suppressed the inflammatory profiles of CFs and reduced the relative ratios and pro-inflammatory signatures of cardiac macrophages. Moreover, fluorescence-activated cell sorting analysis (FACS) revealed that cardiac reprogramming reduced the number of chemokine receptor type 2 (CCR2)-positive inflammatory macrophages in the non-infarct areas in chronic MI, thereby restoring myocardial remodeling. Thus, cardiac reprogramming reduced the number of inflammatory macrophages to exacerbate cardiac function after MI.

Triggers of Ventricular Fibrillation in Patients With Inferolateral J-Wave Syndrome.

BACKGROUND: There are few data on ventricular fibrillation (VF) initiation in patients with inferolateral J waves. OBJECTIVES: This multicenter study investigated the characteristics of triggers initiating spontaneous VF in inferolateral J-wave syndrome. METHODS: A total of 31 patients (age 37 ± 14 years, 24 male) with spontaneous VF episodes associated with inferolateral J waves were evaluated to determine the origin and characteristics of triggers. The J-wave pattern was recorded in inferior leads in 11 patients, lateral leads in 3, and inferolateral leads in 17. RESULTS: The VF triggers (n = 37) exhibited varying QRS durations (176 ± 21 milliseconds, range 119-219 milliseconds) and coupling intervals (339 ± 46 milliseconds, range 250-508 milliseconds) with a right (70%) or left (30%) bundle branch block (BBB) pattern. Trigger patterns were associated with J-wave location: left BBB triggers with inferior J waves and right BBB triggers with lateral J waves. Electrophysiologic study was performed for 22 VF triggers in 19 patients. They originated from the left or right Purkinje system in 6 and from the ventricular myocardium in 10 and were undetermined in 6. Purkinje vs myocardial triggers showed distinct electrocardiographic characteristics in coupling interval and QRS-complex duration and morphology. Abnormal epicardial substrate associated with fragmented electrograms was identified in 9 patients, with triggers originating from the same region in 7 patients. Catheter ablation resulted in VF suppression in 15 patients (79%). CONCLUSIONS: VF initiation in inferolateral J-wave syndrome is associated with significant individual heterogeneity in trigger characteristics. Myocardial triggers have electrocardiographic features distinct from Purkinje triggers, and their origin often colocalizes with an abnormal epicardial substrate.

Instant subacute stent thrombosis after maximum-load cardiopulmonary exercise test in a clopidogrel poor metabolizer with acute coronary syndrome.

A 63-year-old man with a hobby of full marathon and triathlon fainted while commuting on a 25-km one-way bicycle trip and was admitted to the hospital after return of spontaneous circulation. The patient was diagnosed with acute coronary syndrome, and contrast-enhanced computed tomography for trauma diagnosis indicated suspicion of liver injury. Although coronary angiography revealed a severe stenotic lesion in the left anterior descending artery, percutaneous coronary intervention (PCI) was deferred because of thrombolysis in myocardial infarction grade 3 flow. Following neurological recovery, the patient was started on dual antiplatelet therapy (aspirin and clopidogrel). On day 11, a 3.0/34-mm Resolute Onyx stent (Medtronic, Dublin, Ireland) was deployed following rotablation. As a pre-discharge evaluation, a maximum-load cardiopulmonary exercise test was performed 8 days after PCI. However, the patient developed stent thrombosis after 2 h. Subsequently, the patient was diagnosed as a clopidogrel poor metabolizer using a blood test. Learning objective: Existing guidelines recommend a cardiopulmonary exercise test (CPET) before or immediately after the discharge of patients with acute coronary syndrome (ACS). However, the safety of the maximum-load CPET has not been established, especially in clopidogrel poor metabolizers with ACS. Acute maximal exercise induces platelet aggregation; therefore, further discussion is needed regarding the timing of CPET, exercise load level, and patient observation post-CPET in ACS patients after stent placement.

Scalable production of homogeneous cardiac organoids derived from human pluripotent stem cells.

Three-dimensional (3D) cultures are known to more closely mimic in vivo conditions compared with 2D cultures. Cardiac spheroids (CSs) and organoids (COs) are useful for 3D tissue engineering and are advantageous for their simplicity and mass production for regenerative therapy and drug discovery. Herein, we describe a large-scale method for producing homogeneous human induced pluripotent stem cell (hiPSC)-derived CSs (hiPSC-CSs) and COs without scaffolds using a porous 3D microwell substratum with a suction system. Our method has many advantages, such as increased efficiency and improved functionality, homogeneity, and sphericity of hiPSC-CSs. Moreover, we have developed a substratum on a clinically relevant large scale for regenerative therapy and have succeeded in producing approximately 40,000 hiPSC-CSs with high sphericity at once. Furthermore, we efficiently produced a fused CO model consisting of hiPSC-derived atrial and ventricular cardiomyocytes localized on opposite sides of one organoid. This method will facilitate progress toward hiPSC-based clinical applications.