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Background: Polypharmacy is associated with an increased risk of adverse events due to the higher number of drugs used. This is particularly notable in patients with chronic coronary syndrome (CCS), who are known to use a large number of drugs. Therefore, we investigated polypharmacy in patients with CCS, using CLIDAS, a multicenter database of patients who underwent percutaneous coronary intervention. Method and results: Between 2017 and 2020, 1411 CCS patients (71.5 ± 10.5 years old; 77.3 % male) were enrolled. The relationship between cardiovascular events occurring during the median follow-up of 514 days and the number of drugs at the time of PCI was investigated. The median number of drugs prescribed was nine. Major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, stroke, heart failure, transient ischemic attack, or unstable angina, occurred in 123 patients, and all-cause mortality occurred in 68 patients. For each additional drug, the adjusted hazard ratios for MACE and all-cause mortality increased by 2.069 (p = 0.003) and 1.102 (p = 0.010). The adjusted hazard ratios for MACE and all-cause mortality were significantly higher in the group using nine or more drugs compared to the group using eight or fewer drugs (1.646 and 2.253, both p

Abstract Background The precise details of atrial activation around the triangle of Koch (ToK) remain unknown. We evaluated the relationship between the atrial‐activation pattern around the ToK and success sites for slow‐pathway (SP) modification ablation in slow‐fast atrioventricular reentrant tachycardia (AVNRT). Methods Thirty patients with slow‐fast AVNRT who underwent successful ablation were enrolled. Atrial activation around the ToK during sinus rhythm was investigated using ultra‐high‐density mapping pre‐ablation. The relationships among features of atrial‐activation pattern and success sites were examined. Results Of 30 patients (22 cryoablation; 8 radiofrequency ablation), 26 patients had a collision site of two wavefronts of delayed atrial activation within ToK, indicating a success site. The activation‐search function of Lumipoint software, which highlights only atrial activation with a spatiotemporal consistency, showed non‐highlighted area on the tricuspid‐annulus side of ToK. In 23 of the patients, a spiky potential was recorded at that collision site outside the Lumipoint‐highlighted area. Fifteen cryoablation patients with a success site coincident with a collision site outside the Lumipoint‐highlighted area had significantly more frequent disappearances of SP after initial cryoablation (46.7% vs. 0%, p = .029), fewer cryoablations (3.7 ± 1.8 vs. 5.3 ± 1.3, p = .045), and shorter procedure times (170 ± 57 vs. 228 ± 91 min, p = .082) compared to the seven cryoablation patients without such sites. Four patients had transient AV block by ablation inside the Lumipoint‐highlighted area with fractionated signals, but no patient developed permanent AV block or recurrence post‐procedure (median follow‐up: 375 days). Conclusions SP modification ablation at the collision site of atrial activation of the tricuspid‐annulus side along with a spiky potential could provide a better outcome.

Abstract Background While most VVI pacemakers in bradycardic patients are set to a low limit of 60/min, the optimal lower limit rate for VVI pacemakers in atrial fibrillation has not been established. Although an increase in heart rate within the normal range in the setting of a VVI pacemaker might be expected to lead to an increase in cardiac output with the shortening of the diastolic time, the changes in cardiac output at different pacemaker settings have not been fully clarified. Methods We included 11 patients with bradycardic atrial fibrillation who had VVI pacemakers implanted. Stroke volume was measured using the electrical cardiometry method (AESCULONⓇ mini; Osypka Medical) without pacing and at ventricular pacings of 60, 70, 80, and 90/min. Results Stroke volume decreased stepwise at ventricular pacing rates of 60, 70, 80, and 90/min (63.6 ± 11.2, 61.9 ± 10.6, 59.3 ± 12.2, and 57.5 ± 12.2 mL, p

Objective This study aimed to investigate the association between heart failure (HF) severity measured based on brain natriuretic peptide (BNP) levels and future bleeding events after percutaneous coronary intervention (PCI).Background The Academic Research Consortium for High Bleeding Risk presents a bleeding risk assessment for antithrombotic therapy in patients after PCI. HF is a risk factor for bleeding in Japanese patients.Methods Using an electronic medical record-based database with seven tertiary hospitals in Japan, this retrospective study included 7160 patients who underwent PCI between April 2014 and March 2020 and who completed a 3-year follow-up and were divided into three groups: no HF, HF with high BNP level and HF with low BNP level. The primary outcome was bleeding events according to the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries classification of moderate and severe bleeding. The secondary outcome was major adverse cardiovascular events (MACE). Furthermore, thrombogenicity was measured using the Total Thrombus-Formation Analysis System (T-TAS) in 536 consecutive patients undergoing PCI between August 2013 and March 2017 at Kumamoto University Hospital.Results Multivariate Cox regression showed that HF with high BNP level was significantly associated with bleeding events, MACE and all-cause death. In the T-TAS measurement, the thrombogenicity was lower in patients with HF with high BNP levels than in those without HF and with HF with low BNP levels.Conclusions HF with high BNP level is associated with future bleeding events, suggesting that bleeding risk might differ depending on HF severity.

Background: Heart failure (HF) is associated with a high bleeding risk after percutaneous coronary intervention (PCI). Additionally, major bleeding events increase the risk of subsequent major adverse cardiac events (MACE). However, whether brain natriuretic peptide (BNP) levels and major bleeding events following PCI are associated with MACE and all-cause death remains unknown. This study aimed to investigate the impact of HF severity or bleeding on subsequent MACE and all-cause death. Methods: The Clinical Deep Data Accumulation System (CLIDAS), a multicenter database involving seven hospitals in Japan, was developed to collect data from electronic medical records. This retrospective analysis included 7160 patients who underwent PCI between April 2014 and March 2020 and completed a three-year follow-up. Patients were divided according to the presence of HF with high BNP (HFhBNP) (>100 pg/ml) and major bleeding events within 30 days post-PCI (30-day bleeding): HFhBNP with bleeding (n = 14), HFhBNP without bleeding (n = 370), non-HFhBNP with bleeding (n = 74), and non-HFhBNP without bleeding (n = 6702). Results: In patients without 30-day bleeding, HFhBNP was a risk factor for MACE (hazard ratio, 2.19; 95% confidence interval, 1.56–3.07) and all-cause death (hazard ratio, 1.60; 95% confidence interval, 1.60–2.23). Among HFhBNP patients, MACE incidence was higher in patients with 30-day bleeding than in those without bleeding, but the difference was not significant (p = 0.075). The incidence of all-cause death was higher in patients with bleeding (p = 0.001). Conclusions: HF with high BNP and bleeding events in the early stage after PCI might be associated with subsequent MACE and all-cause death.

Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) has a detrimental effect on long-term kidney graft survival. However, the pathogenesis of TAC nephrotoxicity remains largely unknown. We explored it by focusing on metabolic changes in renal tissues. In this study, mice were separated into TAC and control groups (n = 5/group). TAC was administered to the TAC group (1 mg/kg/d for 28 days) subcutaneously. The control group was similarly treated with normal saline. Renal tissue metabolomes were evaluated. Renal fibrosis was observed only in the TAC group. Metabolomic analysis showed that carnitine and related metabolites were substantially lower in the TAC group than in the control group, presumably due to impaired biosynthesis and reabsorption. Low carnitine levels impair antioxidation in renal tissues and β-oxidation in mitochondria, which may lead to renal tissue damage. This metabolomic analysis revealed that carnitine deficiency in renal tissue appears to explain TAC nephrotoxicity.

Abstract Pathogenic variants in myosin heavy chain (Myh11) cause familial thoracic aortic aneurysms and dissections (FTAAD). However, the underlying pathological mechanisms remain unclear because of a lack of animal models. In this study, we established a mouse model with Myh11 K1256del, the pathogenic variant we found previously in two FTAAD families. The Myh11 ∆K/∆K aorta showed increased wall thickness and ultrastructural abnormalities, including weakened cell adhesion. Notably, the Myh11 ∆K/+ mice developed aortic dissections and intramural haematomas when stimulated with angiotensin II. Mechanistically, integrin subunit alpha2 (Itga2) was downregulated in the Myh11 ∆K/∆K aortas, and the smooth muscle cell lineage cells that differentiated from Myh11 ∆K/∆K induced pluripotent stem cells. The contractility of the Myh11 ∆K/∆K aortas in response to phenylephrine was also reduced. These results imply that the suboptimal cell adhesion indicated by Itga2 downregulation causes a defect in the contraction of the aorta. Consequently, the defective contraction may increase the haemodynamic stress underlying the aortic dissections.

Several genetic defects, including a mutation in myosin heavy chain 11 (Myh11), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (Myh11ΔK/ΔK) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca2+ concentration—multiple calcium channel expression and ADP–ribose synthesis—were attenuated in Myh11ΔK/ΔK aortas. We suggest that the impairment of the Ca2+ influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection.

BackgroundThe causal relationship between hyperuricemia and cardiovascular diseases is still unknown. We hypothesized that hyperuricemic patients after percutaneous coronary intervention (PCI) had a higher risk of major adverse cardiovascular events (MACE).MethodsThis was a large-scale multicenter cohort study. We enrolled patients with chronic coronary syndrome (CCS) after PCI between April 2013 and March 2019 using the database from the Clinical Deep Data Accumulation System (CLIDAS), and compared the incidence of MACE, defined as a composite of cardiovascular death, myocardial infarction, and hospitalization for heart failure, between hyperuricemia and non-hyperuricemia groups.ResultsIn total, 9,936 patients underwent PCI during the study period. Of these, 5,138 patients with CCS after PCI were divided into two group (1,724 and 3,414 in the hyperuricemia and non-hyperuricemia groups, respectively). The hyperuricemia group had a higher prevalence of hypertension, atrial fibrillation, history of previous hospitalization for heart failure, and baseline creatinine, and a lower prevalence of diabetes than the non-hyperuricemia group, but the proportion of men and age were similar between the two groups. The incidence of MACE in the hyperuricemia group was significantly higher than that in the non-hyperuricemia group (13.1 vs. 6.4%, log-rank P < 0.001). Multivariable Cox regression analyses revealed that hyperuricemia was significantly associated with increased MACE [hazard ratio (HR), 1.52; 95% confidential interval (CI), 1.23–1.86] after multiple adjustments for age, sex, body mass index, estimated glomerular filtration rate, left main disease or three-vessel disease, hypertension, diabetes mellitus, dyslipidemia, history of myocardial infarction, and history of hospitalization for heart failure. Moreover, hyperuricemia was independently associated with increased hospitalization for heart failure (HR, 2.19; 95% CI, 1.69–2.83), but not cardiovascular death or myocardial infarction after multiple adjustments. Sensitive analyses by sex and diuretic use, B-type natriuretic peptide level, and left ventricular ejection fraction showed similar results.ConclusionCLIDAS revealed that hyperuricemia was associated with increased MACE in patients with CCS after PCI. Further clinical trials are needed whether treating hyperuricemia could reduce cardiovascular events or not.

Background: Surgical pulmonary valve replacement (PVR) is the standard cardiac operation in adult patients with congenital heart disease (ACHD). We report recent experience at a large tertiary centre and examine the impact of prosthesis type on outcomes. Methods: All surgical PVRs performed at our tertiary centre between January 2003 and December 2018 were included. Results: The study population included 490 patients (197 women; mean age 29.9 ± 13 years). The types of valves used were Homograft 179 (37%), Perimount 152 (31%), Mosaic 120 (24%), Hancock 31 (6%), and others 5 (1%). Seven (1.4%) early deaths occurred within 30 days after surgery. The survival rates at 1, 5, 10, and 15 years of follow-up were 98.3%, 97.7%, 96.8%, and 95.4%, respectively, whereas freedom from re-intervention was 99.8%, 96.6%, 90.2%, and 81.0%, respectively. During a mean follow-up of 6.5 ± 4.3 years, 27 (5.5%) patients required re-intervention. The type of valve used in these 27 patients during index operation showed no discernible difference in the probability of re-intervention; however, Mosaic valves required earlier re-intervention compared to Perimount valves. Conclusion: Our data show no discernible difference in reoperation rates between the different types of prostheses used. On-going surveillance of patients after PVR and further research in developing a life-long prosthesis are clearly warranted.

Abstract In heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes β-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, β-MHC, and β-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/β-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.

Abstract Aims The aim of this study was to investigate whether ethnicity influences the associations between trimethylamine N‐oxide (TMAO) levels and heart failure (HF) outcomes. Methods and results Trimethylamine N‐oxide levels were measured in two cohorts with acute HF at two sites. The UK Leicester cohort consisted mainly of Caucasian (n = 842, 77%) and South Asian (n = 129, 12%) patients, whereas patients in the Japanese cohort (n = 116, 11%) were all Japanese. The primary endpoint was the measurement of all‐cause mortality and/or HF rehospitalization within 1 year post‐admission. Association of TMAO levels with outcome was compared in the entire population and between ethnic groups after adjustment for clinical parameters. TMAO levels were significantly higher in Japanese patients [median (interquartile range): 9.9 μM (5.2–22.8)] than in Caucasian [5.9 μM (3.6–10.8)] and South Asian [4.5 μM (3.1–8.4)] (P

Objective To examine the association between polarity of atrial premature complexes (APCs) and stroke.Design A prospective study.Setting and participants A total of 11 092 participants in the Jichi Medical School cohort study were included after excluding patients with atrial fibrillation. We analysed stroke events in patients with (n=136) and without (n=10 956) APCs. With regard to polarity of APCs, patients were subcategorised into having (1) negative (n=39) or non-negative (n=97) P waves in augmented vector right (aVR), and (2) positive (n=28) or non-positive (n=108) P waves in augmented vector left (aVL).Outcome measures The primary endpoint was stroke.Results Patients with APCs were significantly older than those without APCs (64.1±9.2 vs 55.1±11.6 years, p

We report on a 64-year-old female patient who underwent cardiac surgery for left atrial myxoma, using the superior septal approach with large atrial septal wall resection and patch closure. The superior septal approach is reported to be a relatively safe method for preventing the development of sinus node dysfunction after cardiac surgery. However, this patient developed sinus node dysfunction after surgery and required the implantation of a permanent pacemaker. Moreover, in this case, determining the appropriate positions of the pacemaker leads was difficult because of the presence of a large conduction delay in the interatrium. Selecting the appropriate atrioventricular delay settings was important in order to achieve proper sequential contractions between the left atrium and the left ventricle.

Immunoglobulin light chain (AL) amyloidosis has poor long-term prognosis. Sudden cardiac death (SCD) is a common cause of death in patients with cardiac AL amyloidosis. Prophylactic anti-arrhythmic device therapy has been suggested as an option to reduce this risk. We address this issue by reviewing 4 cases of cardiac AL amyloidosis with anti-arrhythmic device therapy. One patient who had an atrioventricular block underwent pacemaker implantation, and the other 3 patients received implantable cardioverter-defibrillator (ICD) implantation for ventricular arrhythmia. All of the 3 ICD implantation cases received appropriate shock therapy for ventricular arrhythmia in the early stage. However, they soon died due to pulseless electrical activity (PEA) or severe heart failure. The median survival period for our 4 cases was as short as 12.3 months. In particular, the 3 patients who required ICD had worse prognoses. Thus, ICD implantation therapy for chemotherapy-resistant cardiac AL amyloidosis may prevent SCD but may not prolong the patient's survival. There are no arguments against pacemaker implantation for cardiac amyloidosis with conduction disturbance; however, the clinical benefit of ICD indication for ventricular tachyarrhythmia is limited. Further extensive clinical research should be performed to definitively determine the effects of ICD implantation on cardiac AL amyloidosis.

The aim of this study was to evaluate the validity and reliability of the Seattle Angina Questionnaire, Japanese version (SAQ-J) as a disease-specific health outcome scale in patients with coronary artery disease. Methods: Patients with coronary artery disease were recruited from a university hospital in Tokyo. The patients completed self-administered questionnaires, and medical information was obtained from the subjects' medical records. Face validity, concurrent validity evaluated using Short Form 36 (SF-36), known group differences, internal consistency, and test-retest reliability were statistically analyzed. Results: A total of 354 patients gave informed consent, and 331 of them responded (93.5%). The concurrent validity was mostly supported by the pattern of association between SAQ-J and SF-36. The patients without chest symptoms showed significantly higher SAQ-J scores than did the patients with chest symptoms in 4 domains. Cronbach's alpha ranged from .51 to .96, meaning that internal consistency was confirmed to a certain extent. The intraclass correlation coefficient of most domains was higher than the recommended value of 0.70. The weighted kappa ranged from .24 to .57, and it was greater than .4 for 14 of the 19 items. Conclusions: The SAQ-J could be a valid and reliable disease-specific scale in some part for measuring health outcomes in patients with coronary artery disease, and requires cautious use.

Continuous monitoring of blood pressure in daily life could improve early detection of cardiovascular disorders, as well as promoting healthcare. Conventional ambulatory blood pressure monitoring (ABPM) equipment can measure blood pressure at regular intervals for 24 hours, but is limited by long measuring time, low sampling rate, and constrained measuring posture. In this paper, we demonstrate a new method for continuous real-time measurement of blood pressure during daily activities. Our method is based on blood pressure estimation from pulse wave velocity (PWV) calculation, which formula we improved to take into account changes in the inner diameter of blood vessels. Blood pressure estimation results using our new method showed a greater precision of measured data during exercise, and a better accuracy than the conventional PWV method.

BACKGROUND: Although periodontitis is a risk factor for cardiovascular disease (CVD), the influence of periodontitis on Marfan syndrome (MFS) with CVD is unclear. The aim of this study was to assess the relationship between periodontal bacterial burden and MSF with CVD. METHODS AND RESULTS: The subjects were patients with MFS with CVD (n = 47); age and gender matched non-MFS CVD patients (n = 48) were employed as controls. Full-mouth clinical measurements, including number of teeth, probing of pocket depth (PD), bleeding on probing (BOP) and community periodontal index (CPI) were recorded. We also evaluated the existence of three periodontal pathogens, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia using polymerase chain reaction assays. Serum antibody titers against the pathogens were also measured. We revealed that MFS with CVD patients had periodontitis more frequently than the age and gender matched non-MFS CVD control subjects. MFS with CVD patients had significantly severer periodontitis, fewer remaining teeth and deeper PD compared to the non-MFS CVD controls. Furthermore, the serum antibody titer level against Prevotella intermedia was significantly lower in MFS plus CVD patients compared to the non-MFS CVD patients. CONCLUSION: Periodontitis may influence the pathophysiology of cardiovascular complications in MFS patients. A specific periodontal pathogen might be a crucial therapeutic target to prevent CVD development.

Coronary artery disease (CAD) is a multifactorial disease with environmental and genetic determinants. The genetic determinants of CAD have previously been explored by the candidate gene approach. Recently, the data from the International HapMap Project and the development of dense genotyping chips have enabled us to perform genome-wide association studies (GWAS) on a large number of subjects without bias towards any particular candidate genes. In 2007, three chip-based GWAS simultaneously revealed the significant association between common variants on chromosome 9p21 and CAD. This association was replicated among other ethnic groups and also in a meta-analysis. Further investigations have detected several other candidate loci associated with CAD. The chip-based GWAS approach has identified novel and unbiased genetic determinants of CAD and these insights provide the important direction to better understand the pathogenesis of CAD and to develop new and improved preventive measures and treatments for CAD.