Toya, Takumi

Background: The majority of randomized controlled trials of revascularization decision-making excludes left main coronary artery disease (LMD). Therefore, contemporary clinical outcomes of patients with stable coronary artery disease and LMD with proven ischemia remain poorly understood. The aim of this study was to assess the long-term clinical outcomes of physiologically significant LMD according to the treatment strategies of revascularization versus revascularization deferral. Methods: In this international multicenter registry of stable LMD interrogated with the instantaneous wave-free ratio, patients with physiologically significant ischemia (instantaneous wave-free ratio ≤0.89) were analyzed according to the coronary revascularization (n=151) versus revascularization deferral (n=74). Propensity score matching was performed to adjust for baseline clinical characteristics. The primary end point was a composite of death, nonfatal myocardial infarction, and ischemia-driven target lesion revascularization of left main stem. The secondary end points were as follows: cardiac death or spontaneous LMD-related myocardial infarction; and ischemia-driven target lesion revascularization of left main stem. Results: At a median follow-up period of 2.8 years, the primary end point occurred in 11 patients (14.9%) in the revascularized group and 21 patients (28.4%) in the deferred group (hazard ratio, 0.42 [95% CI, 0.20–0.89]; P =0.023). For the secondary end points, cardiac death or LMD-related myocardial infarction occurred significantly less frequently in the revascularized group (0.0% versus 8.1%; P =0.004). The rate of ischemia-driven target lesion revascularization of left main stem was also significantly lower in the revascularized group (5.4% versus 17.6%; hazard ratio, 0.20 [95% CI, 0.056–0.70]; P =0.012). Conclusions: In patients who underwent revascularization for stable coronary artery disease and physiologically significant LMD determined by instantaneous wave-free ratio, the long-term clinical outcomes were significantly improved as compared with those in whom revascularization was deferred.

Introduction: Peripheral microvascular endothelial dysfunction (PMED) is a marker and precursor of atherosclerosis and is associated with an increased risk of cardiovascular events. The present study aims to identify the best cut-off value of PMED, assessed by the reactive hyperemia index, in predicting major adverse cardiovascular events (MACE). Additionally, we investigate whether integrating PMED to CHA2DS2-Vasc score improves the predicting accuracy of cardiovascular disease. Methods: this is a retrospective study of patients who underwent reactive hyperemia peripheral arterial tonometry (PAT). The optimal cut-off value of reactive hyperemia index associated with MACE was calculated using the area under the receiver-operating curve and the maximum Youden index. Traditional cardiovascular risk factors such as age, sex, congestive heart failure, hypertension, diabetes, stroke, vascular disease were determined to calculate the CHA2DS2-VASc score. MACE was defined as myocardial infarction, heart failure hospitalization, and cerebrovascular events. Results: 1,690 patients were enrolled (average age 51.1±13.9, 64.1% female). The optimal cut-off value of the reactive hyperemia index was 2.0 in the overall population and females and 2.17 in males. The risk of MACE during 10 (Interquartile range: 4,16) years of follow-up was 15.3%. Multivariable logistic regression revealed that PMED as an independent predictor of MACE (PMED: OR, 3.6, 95% CI, 2.6-4.9, p<0.001) (Table1). Furthermore, integrating PMED to CHA2DS2-VASc significantly improved the predictive accuracy (area under the curve, 0.747 vs. 0.708, p<0.001). Conclusion: PMED is a strong predictor of cardiovascular events. Non-invasive assessment of peripheral endothelial function may be useful in early detection and improving the stratification of high-risk patients for cardiovascular events.

Introduction: Mechanisms underlying bioprosthetic valve deterioration (BVD) are multifactorial and incompletely elucidated. Reparative circulating progenitor cells (CPCs), and conversely calcification-associated osteocalcin expressing CPCs (CPC-OCN), have been linked to native aortic valve deterioration. However, their role in BVD remains elusive. This study sought to evaluate the contribution of different subpopulations of CPCs in BVD. Methods: This prospective study enrolled 121 patients who had peripheral blood mononuclear cells (PBMC) isolated prior to bioprosthetic aortic valve replacement (surgical 104, transcatheter 17) and had an echocardiographic follow-up ≥2 years after the procedure. Using flow cytometry, fresh PBMC were analyzed for the surface markers CD34, CD133, and osteocalcin (OCN). BVD was evaluated by hemodynamic valve deterioration (HVD) using echocardiography, which was defined as an elevated mean transprosthetic gradient ≥30mmHg and/or at least moderate intraprosthetic regurgitation. Multivariable models were constructed to evaluate the association of each subpopulation of CPCs and other clinical characteristics with HVD. Results: Sixteen patients (13.2%) developed HVD during follow-up for a median of 5.9 years. Patients with HVD showed significantly lower levels of reparative CD34 + CD133 + cells and higher levels of OCN + cells than those without HVD (CD34 + CD133 + cells: 125 [80, 210] vs 270 [130, 420], P=0.002; OCN + cells: 3060 [523, 5528] vs 670 [180, 1930], P=0.005 respectively). Decreased level of CD34 + CD133 + cells was a significant predictor of HVD. Conclusions: Circulating levels of CD34 + CD133 + cells and OCN + cells were significantly associated with the subsequent occurrence of HVD in patients undergoing bioprosthetic aortic valve replacement. CPCs might play a vital role in the mechanism, risk stratification and a potential therapeutic target for patients with bioprosthetic valve deterioration.

AbstractIntroductionData regarding ventricular tachycardia (VT) or premature ventricular complex (PVC) ablation in patients with aortic valve (AV) intervention (AVI) is limited. Catheter ablation (CA) can be challenging given perivalvular substrate in the setting of prosthetic valves. We sought to investigate the characteristics, safety, and outcomes of CA in patients with prior AVI and ventricular arrhythmias (VA).MethodsWe identified consecutive patients with prior AVI (replacement or repair) who underwent CA for VT or PVC between 2013 and 2018. We investigated the mechanism of arrhythmia, ablation approach, perioperative complications, and outcomes.ResultsWe included 34 patients (88% men, mean age 64 ± 10.4 years, left ventricular (LV) ejection fraction 35.2 ± 15.0%) with prior AVI who underwent CA (22 VT; 12 PVC). LV access was obtained through trans‐septal approach in all patients except one patient who had percutaneous transapical access. One patient had combined retrograde aortic and trans‐septal approach. Scar‐related reentry was the dominant mechanism of induced VTs. Two patients had bundle branch reentry VTs. In the VT group, substrate mapping demonstrated heterogeneous scar that involved the peri‐AV area in 95%. Despite that, the site of successful ablation included the periaortic region only in 6 (27%) patients. In the PVC group, signal abnormalities consistent with scar in the periaortic area were noted in 4 (33%) patients. In 8 (67%) patients, the successful site of ablation was unrelated to the periaortic area. No procedure‐related complications occurred. The survival and recurrence‐free survival rate at 1 year tended to be lower in VT group than in PVC group (p = .06 and p = .05, respectively) with a 1‐year recurrence‐free survival rate of 52.8% and 91.7%, respectively. No arrhythmia‐related death was documented on long‐term follow‐up.ConclusionCA of VAs can be performed safely and effectively in patients with prior AVI.

Background: Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is a risk factor for cardiovascular disease. The relationship between CHIP and coronary microvascular dysfunction (CMD) is unknown. The current study examines the association between CHIP and CH with CMD and the potential relationships in risk for adverse cardiovascular outcomes. Methods: In this retrospective observational study, targeted next-generation sequencing was performed for 177 participants with no coronary artery disease who presented with chest pain and underwent routine coronary functional angiogram. Patients with somatic mutations in leukemia-associated driver genes in hematopoietic stem and progenitor cells were examined; CHIP was considered at a variant allele fraction ≥2%; CH was considered at a variant allele fraction ≥1%. CMD was defined as coronary flow reserve to intracoronary adenosine of ≤2. Major adverse cardiovascular events considered were myocardial infarction, coronary revascularization, or stroke. Results: A total of 177 participants were examined. Mean follow-up was 12±7 years. A total of 17 patients had CHIP and 28 had CH. Cases with CMD (n=19) were compared with controls with no CMD (n=158). Cases were 56±9 years, were 68% women, and had more CHIP (27%; P =0.028) and CH (42%; P =0.001) than controls. CMD was associated with independent risk for major adverse cardiovascular events (hazard ratio, 3.89 [95% CI, 1.21–12.56]; P =0.023), and 32% of this risk was mediated by CH. The risk mediated by CH was ≈0.5× as large as the direct effect of CMD on major adverse cardiovascular events. Conclusions: In humans, we observe patients with CMD are more likely to have CHIP, and nearly one-third of major adverse cardiovascular events in CMD are mediated by CH.

Background Mechanisms underlying bioprosthetic valve deterioration are multifactorial and incompletely elucidated. Reparative circulating progenitor cells, and conversely calcification‐associated osteocalcin expressing circulating progenitor cells, have been linked to native aortic valve deterioration. However, their role in bioprosthetic valve deterioration remains elusive. This study sought to evaluate the contribution of different subpopulations of circulating progenitor cells in bioprosthetic valve deterioration. Methods and Results This single‐center prospective study enrolled 121 patients who had peripheral blood mononuclear cells isolated before bioprosthetic aortic valve replacement and had an echocardiographic follow‐up ≥2 years after the procedure. Using flow cytometry, fresh peripheral blood mononuclear cells were analyzed for the surface markers CD34, CD133, and osteocalcin. Bioprosthetic valve deterioration was evaluated by hemodynamic valve deterioration (HVD) using echocardiography, which was defined as an elevated mean transprosthetic gradient ≥30 mm Hg or at least moderate intraprosthetic regurgitation. Sixteen patients (13.2%) developed HVD during follow‐up for a median of 5.9 years. Patients with HVD showed significantly lower levels of reparative CD34 + CD133 + cells and higher levels of osteocalcin‐positive cells than those without HVD (CD34 + CD133 + cells: 125 [80, 210] versus 270 [130, 420], P =0.002; osteocalcin‐positive cells: 3060 [523, 5528] versus 670 [180, 1930], P =0.005 respectively). Decreased level of CD34 + CD133 + cells was a significant predictor of HVD (hazard ratio, 0.995 [95% CI, 0.990%–0.999%]). Conclusions Circulating levels of CD34 + CD133 + cells and osteocalcin‐positive cells were significantly associated with the subsequent occurrence of HVD in patients undergoing bioprosthetic aortic valve replacement. Circulating progenitor cells might play a vital role in the mechanism, risk stratification, and a potential therapeutic target for patients with bioprosthetic valve deterioration.

In recent years, the importance of the gut microbiome in human health and disease has increased. Growing evidence suggests that gut dysbiosis might be a crucial risk factor for coronary artery disease (CAD). Therefore, we conducted a systematic review and meta-analysis to determine whether or not CAD is associated with specific changes in the gut microbiome. The V3–V4 regions of the 16S rDNA from fecal samples were analyzed to compare the gut microbiome composition between CAD patients and controls. Our search yielded 1181 articles, of which 21 met inclusion criteria for systematic review and 7 for meta-analysis. The alpha-diversity, including observed OTUs, Shannon and Simpson indices, was significantly decreased in CAD, indicating the reduced richness of the gut microbiome. The most consistent results in a systematic review and meta-analysis pointed out the reduced abundance of Bacteroidetes and Lachnospiraceae in CAD patients. Moreover, Enterobacteriaceae, Lactobacillus, and Streptococcus taxa demonstrated an increased trend in CAD patients. The alterations in the gut microbiota composition are associated with qualitative and quantitative changes in bacterial metabolites, many of which have pro-atherogenic effects on endothelial cells, increasing the risk of developing and progressing CAD.

AbstractAimsAn artificial intelligence algorithm detecting age from 12-lead electrocardiogram (ECG) has been suggested to reflect ‘physiological age’. An increased physiological age has been associated with a higher risk of cardiac mortality in the non-transplant population. We aimed to investigate the utility of this algorithm in patients who underwent heart transplantation (HTx).Methods and resultsA total of 540 patients were studied. The average ECG ages within 1 year before and after HTx were used to represent pre- and post-HTx ECG ages. Major adverse cardiovascular event (MACE) was defined as any coronary revascularization, heart failure hospitalization, re-transplantation, and mortality. Recipient pre-transplant ECG age (mean 63 ± 11 years) correlated significantly with recipient chronological age (mean 49 ± 14 years, R = 0.63, P &lt; 0.0001), while post-transplant ECG age (mean 54 ± 10 years) correlated with both the donor (mean 32 ± 13 years, R = 0.45, P &lt; 0.0001) and the recipient ages (R = 0.38, P &lt; 0.0001). During a median follow-up of 8.8 years, 307 patients experienced MACE. Patients with an increase in ECG age post-transplant showed an increased risk of MACE [hazard ratio (HR): 1.58, 95% confidence interval (CI): (1.24, 2.01), P = 0.0002], even after adjusting for potential confounders [HR: 1.58, 95% CI: (1.19, 2.10), P = 0.002].ConclusionElectrocardiogram age-derived cardiac ageing after transplantation is associated with a higher risk of MACE. This study suggests that physiological age change of the heart might be an important determinant of MACE risk post-HTx.

Abstract Aims Cardiovascular disease and cancer share common pathogenesis and risk factors. Coronary microvascular dysfunction (CMD), reflecting impaired coronary microvascular dilation in response to stress, is related to a higher risk of major cardiovascular events; however, its association with cancer has not been explored. Methods and results A retrospective study on 1042 patients with non-obstructive coronary artery diseases (NOCADs) was performed. Data regarding demographic, clinical history, diagnostic coronary reactivity test, and cancer occurrence were collected. Coronary microvascular dysfunction was defined as coronary flow reserve (the ratio of hyperaemic blood flow to resting blood flow) ≤2.5. Thirty-four per cent had CMD (67.4% female and the average age was 52.4 ± 12.2 years). Of 917 patients with no history of cancer, 15.5% developed cancer during follow-up [median of 9 (4, 16) years]. Kaplan–Meier analysis showed that CMD patients had lower cancer-free survival compared with those without CMD (log-rank P = 0.005). Cox proportional hazard analyses showed that after adjusting for age, sex, hypertension, diabetes, smoking, and glomerular filtration rate, CMD is independently associated with cancer [hazard ratio, 1.4; 95% confidence interval (CI), 1.09–2.04; P = 0.04]. The rate of major adverse cardiovascular events (MACE) was significantly higher in CMD patients compared with that in non-CMD patients who had a previous history of cancer [odds ratio (OR), 2.5; 95% CI, 1–6.2; P = 0.04] and those with no history of cancer (OR, 1.4; 95% CI, 1.01–1.9; P = 0.044). Conclusion Coronary microvascular dysfunction is associated with cancer incidence in patients presenting with NOCADs. This study emphasizes follow-up in patients with CMD to evaluate the risk of MACE as well as potential malignant diseases.