Impact of baseline yellow plaque assessed by coronary angioscopy on vascular response after stent implantation.

BACKGROUND: The relationship between baseline yellow plaque (YP) and vascular response after stent implantation has not been fully investigated. METHODS: This was a sub-analysis of the Collaboration-1 study (multicenter, retrospective, observational study). A total of 88 lesions from 80 patients with chronic coronary syndrome who underwent percutaneous coronary intervention were analyzed. Optical coherence tomography (OCT) and coronary angioscopy (CAS) were serially performed immediately and 11 months after stent implantation. YP was defined as the stented segment with yellow or intensive yellow color assessed by CAS. Neoatherosclerosis was defined as a lipid or calcified neointima assessed by OCT. OCT and CAS findings at 11 months were compared between lesions with baseline YP (YP group) and lesions without baseline YP (Non-YP group). RESULTS: Baseline YP was detected in 37 lesions (42 %). OCT findings at 11 months showed that the incidence of neoatherosclerosis was significantly higher in the YP group (11 % versus 0 %, p = 0.028) and mean neointimal thickness tended to be lower (104 ±â€¯43 µm versus 120 ±â€¯48 µm, p = 0.098). CAS findings at 11 months demonstrated that the dominant and minimum neointimal coverage grades were significantly lower (p = 0.049 and P = 0.026) and maximum yellow color grade was significantly higher (p < 0.001) in the YP group. CONCLUSIONS: Baseline YP affected the incidence of neoatherosclerosis as well as poor neointimal coverage at 11 months after stent implantation.

Pathophysiological insights into machine learning-based subphenotypes of acute heart failure with preserved ejection fraction.

OBJECTIVE: The heterogeneous pathophysiology of the diverse heart failure with preserved ejection fraction (HFpEF) phenotypes needs to be examined. We aim to assess differences in the biomarkers among the phenotypes of HFpEF and investigate its multifactorial pathophysiology. METHODS: This study is a retrospective analysis of the PURSUIT-HFpEF Study (N=1231), an ongoing, prospective, multicentre observational study of acute decompensated HFpEF. In this registry, there is a predefined subcohort in which we perform multibiomarker tests (N=212). We applied the previously established machine learning-based clustering model to the subcohort with biomarker measurements to classify them into four phenotypes: phenotype 1 (n=69), phenotype 2 (n=49), phenotype 3 (n=41) and phenotype 4 (n=53). Biomarker characteristics in each phenotype were evaluated. RESULTS: Phenotype 1 presented the lowest value of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive C reactive protein, tumour necrosis factor-α, growth differentiation factor (GDF)-15, troponin T and cystatin C, whereas phenotype 2, which is characterised by hypertension and cardiac hypertrophy, showed the highest value of these markers. Phenotype 3 showed the second highest value of GDF-15 and cystatin C. Phenotype 4 presented a low NT-proBNP value and a relatively high GDF-15. CONCLUSIONS: Distinctive characteristics of biomarkers in HFpEF phenotypes would indicate differential underlying mechanisms to be elucidated. The contribution of inflammation to the pathogenesis varied considerably among different HFpEF phenotypes. Systemic inflammation substantially contributes to the pathophysiology of the classic HFpEF phenotype with cardiac hypertrophy. TRIAL REGISTRATION NUMBER: UMIN-CTR ID: UMIN000021831.

P2Y12 inhibitor monotherapy after complex percutaneous coronary intervention: a systematic review and meta-analysis of randomized clinical trials.

It remains unknown whether the recent trend of short dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor monotherapy can simply be applied to patients undergoing complex percutaneous coronary intervention (PCI). We performed a systematic review and meta-analysis to evaluate P2Y12 inhibitor monotherapy vs. conventional DAPT in patients undergoing complex PCI and non-complex PCI (PROSPERO: CRD42022335723). Primary endpoint was the 1-year Net Adverse Clinical Event (NACE). Among 5,323 screened studies, six randomized trials fulfilled the eligibility criteria. A total of 10,588 complex PCI patients (5,269 vs. 5,319 patients) and 25,618 non-complex PCI patients (12,820 vs 12,798 patients) were randomly assigned to P2Y12 inhibitor monotherapy vs. conventional DAPT. In complex PCI patients, P2Y12 inhibitor monotherapy was associated with a lower risk of NACE than conventional DAPT [Odds ratio (OR) 0.76, 95% confidence interval (CI) 0.63-0.91, P = 0.003], whereas in non-complex PCI patients, P2Y12 inhibitor monotherapy was associated with a trend toward lowering the risk of NACE (OR 0.86, 95% CI 0.72-1.02, P = 0.09). This meta-analysis across randomized trials demonstrated that a strategy of short DAPT followed by P2Y12 inhibitor monotherapy reduces the risk of 1-year NACE in patients undergoing complex PCI.

Not brushing teeth at night may increase the risk of cardiovascular disease.

In this study, we investigated whether toothbrushing timing affects cardiovascular disease risk. We enrolled 1675 patients aged ≥ 20 years who were hospitalized for surgery, examination, or medical treatment. The participants were categorized as follows based on toothbrushing: Group MN (brushing teeth after waking up and at night, n = 409), Group Night (brushing teeth at night but not upon waking up, n = 751), Group M (brushing teeth after waking up but not at night, n = 164), and Group None (not brushing teeth at all, n = 259). The participants' age, sex, smoking history, and follow-up results were evaluated. Group M had four times as many men as women. Multivariate analysis of cardiovascular events showed significantly higher survival estimates in Group MN (P = 0.021) and Group Night (P = 0.004) than in Group None. Kaplan-Meier analysis of subgroups based on smoking status revealed that smokers in Group None had significantly worse prognosis for cardiovascular onset events than smokers in other groups; non-smokers in Groups None and M showed significantly worse prognosis on hospitalization. Our findings are limited to cardiovascular diseases and cannot be generalized to healthy populations. However, we suggest that brushing teeth at night is important for lowering cardiovascular disease risk.

Relationship Between Canagliflozin, Sodium Glucose Cotransporter 2 Inhibitor, and Hematopoietic Effects in Patients With Diabetes and Mild Heart Failure: Results From the CANDLE Trial.

ABSTRACT: There were few clinical studies on the relationship between sodium glucose cotransporter 2 inhibitors (SGLT2i) and hematopoiesis in patients with diabetes (DM) and heart failure (HF) with consideration of systemic volume status. A total of 226 DM patients with HF enrolled in the CANDLE trial, a multicenter, prospective, randomized open-label blinded-endpoint trial, were studied. Estimated plasma volume status (ePVS) was calculated based on a weight- and hematocrit-based formula. At baseline, there was no significant difference in hematocrit and hemoglobin between the canagliflozin (n = 109) and glimepiride (n = 116) groups. Hematocrit and hemoglobin at 24 weeks, changes in hematocrit and hemoglobin difference (24 weeks-baseline), and hematocrit and hemoglobin ratio (24 weeks/baseline) were significantly higher in the canagliflozin than in the glimepiride group, respectively. There was no significant difference in ePVS at baseline and 24 weeks between the 2 groups. After adjustment for baseline parameters, canagliflozin correlated positively with changes in hematocrit and hemoglobin difference, and hematocrit and hemoglobin ratio by multivariate linear regression analyses. The difference in hematocrit and hemoglobin between the 2 groups became statistically significant at 3 and 6 months after randomization. There was no heterogeneity between canagliflozin and the characteristics of the patients for hematocrit and hemoglobin difference and ratio. A correlation of the changes in hematocrit and hemoglobin with cardiac and renal improvement was not observed. In conclusion, canagliflozin was associated with an increased hematocrit and hemoglobin in patients with diabetes and HF regardless of their volume status and characteristics.

Prognostic impact of cardiovascular polypharmacy on octogenarians with heart failure with preserved ejection fraction.

BACKGROUNDS: Drug treatments of heart failure with preserved ejection fraction (HFpEF) have a little clinical benefit, but cardiovascular polypharmacy (CP) trend is observed in elderly HFpEF. We investigated the impact of CP on octogenarian with HFpEF. METHODS: We examined 783 consecutive octogenarians (≥80 years) enrolled in the PURSUIT-HFpEF registry. We defined medications for hypertension, dyslipidemia, heart failure (HF), coronary artery disease, stroke, peripheral artery disease, and atrial fibrillation as cardiovascular medications (CM). In this study, we defined CP as ≥5 CM. We investigated whether CP was correlated with the composite end point (CE) of all-cause mortality and HF rehospitalization. RESULTS: The proportion with CP was 51.9% (n = 406). Background characteristics correlated with CP were frailty, history of coronary artery disease, atrial fibrillation and left atrial dimension. Multivariable Cox proportional hazards analysis showed CP was significantly and independently correlated with CE (hazard ratio (HR): 1.31; 95% confidence Interval (CI): 1.01-1.70) in addition to age, clinical frailty scale, history of HF admission and N-terminal pro brain natriuretic peptide. Kaplan-Meier curve analysis showed that, compared with the non-CP group, the CP group had significantly higher risk of CE and HF (HR: 1.27; 95%CI: 1.04-1.56; P = 0.02 and HR: 1.46; 95%CI: 1.13-1.88; P < 0.01, respectively), but not any-cause death. In addition, diuretics were correlated with CE (HR: 1.61; 95%CI: 1.17-2.22; P < 0.01), but antithrombotic drugs and HFpEF medications were not. CONCLUSIONS: CP at discharge is a prognostic factor driven by HF rehospitalization in octogenarians with HFpEF. In these patients, diuretics may be correlated with the prognosis.

A Dietary Oxysterol, 7-Ketocholesterol, Exacerbates Imiquimod-Induced Psoriasis-like Dermatitis in Steatohepatitic Mice.

Patients with psoriasis are at a higher risk of developing nonalcoholic fatty liver disease. We previously identified an oxidized derivative of cholesterol, 7-ketocholesterol (7KC), in diet-induced steatohepatitic mice. Here, we investigated whether 7KC exacerbates psoriasis-like dermatitis by accelerating steatohepatitis in mice. A high-fat/high-cholesterol/high-sucrose/bile salt diet (nonalcoholic steatohepatitis (NASH) diet) with or without 0.0125% 7KC was fed to C57BL/6 mice (7KC or control group) for three weeks to induce steatohepatitis. A 5% imiquimod cream was then applied to the ears and dorsal skin for four days to induce psoriasis-like dermatitis. Hepatic lipid accumulation and inflammatory cell infiltration were exacerbated in the 7KC group compared with the control group after three weeks. Serum tumor necrosis factor-α (TNF-α) levels were also elevated in the 7KC group (108.5 ± 9.8 vs. 83.1 ± 13.1 pg/mL, p < 0.005). Imiquimod cream increased the psoriasis area severity index (PASI) score in mice in the 7KC group (9.14 ± 0.75 vs. 5.17 ± 1.17, p < 0.0001). Additionally, Tnfa, Il23a, Il17a, and Il22 mRNA levels in the dorsal lesion were significantly upregulated. Finally, Th17 cell differentiation and the TNF signaling pathway were enhanced in the dorsal lesions and liver of mice in the 7KC group. These data suggest that steatohepatitis and psoriasis are linked by a potent, diet-related factor.

Modeling reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes.

Loss-of-function mutations in PKP2, which encodes plakophilin-2, cause arrhythmogenic cardiomyopathy (AC). Restoration of deficient molecules can serve as upstream therapy, thereby requiring a human model that recapitulates disease pathology and provides distinct readouts in phenotypic analysis for proof of concept for gene replacement therapy. Here, we generated isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with precisely adjusted expression of plakophilin-2 from a patient with AC carrying a heterozygous frameshift PKP2 mutation. After monolayer differentiation, plakophilin-2 deficiency led to reduced contractility, disrupted intercalated disc structures, and impaired desmosome assembly in iPSC-CMs. Allele-specific fluorescent labeling of endogenous DSG2 encoding desmoglein-2 in the generated isogenic lines enabled real-time desmosome-imaging under an adjusted dose of plakophilin-2. Adeno-associated virus-mediated gene replacement of PKP2 recovered contractility and restored desmosome assembly, which was sequentially captured by desmosome-imaging in plakophilin-2-deficient iPSC-CMs. Our isogenic set of iPSC-CMs recapitulates AC pathology and provides a rapid and convenient cellular platform for therapeutic development.

Factors Associated With Prehospital Delay Among Patients With Acute Myocardial Infarction in the Era of Percutaneous Coronary Intervention　- Insights From the OACIS Registry.

BACKGROUND: The Japan Circulation Society launched the STOP-MI campaign in 2014, focusing on immediate hospital arrival for acute myocardial infarction (AMI) treatment. This study aimed to determine the factors influencing longer prehospital time among patients with AMI in Japan.Methods and Results:This study analyzed a total of 4,625 AMI patients enrolled in the Osaka Acute Coronary Insufficiency Study registry from 1998 to 2014. The prehospital time delay was defined as the time interval from the onset of initial symptoms to hospital arrival time ≥2 h. Among eligible patients, 2,927 (63.3%) had a prehospital time ≥2 h. In multivariable analyses, age 65-79 years (adjusted odds ratio [AOR] 1.19, 95% confidence interval [CI] 1.02-1.39), age ≥80 years (AOR 1.42, 95% CI 1.13-1.79), diabetes mellitus (AOR 1.33, 95% CI 1.16-1.52), and onset time of 0:00-5:59 h (AOR 1.63, 95% CI 1.37-1.95) were positively associated with prehospital time ≥2 h, whereas smoking (AOR 0.78, 95% CI 0.68-0.90) and ambulance use (AOR 0.37, 95% CI 0.32-0.43) were negatively associated with prehospital time ≥2 h. CONCLUSIONS: Older age, diabetes mellitus, and nighttime onset were associated with prehospital time delay for AMI patients, whereas smoking and ambulance use were associated with no prehospital time delay. Healthcare providers and patients could help reduce the time to get to a medical facility by being aware of these findings.

Phospholamban p.Arg14del Cardiomyopathy: A Japanese Case Series.

Phospholamban p.Arg14del is reported to cause hereditary cardiomyopathy with malignant ventricular tachycardia (VT) and advanced heart failure. However, the clinical courses of Japanese cardiomyopathy patients with phospholamban p.Arg14del remain uncharacterized. We identified five patients with this variant. All patients were diagnosed with dilated cardiomyopathy (DCM), developed end-stage heart failure and experienced VT requiring implantable cardioverter defibrillator discharge. Four patients survived after implantation of a left ventricular assist device (LVAD), while one patient who refused LVAD implantation died of heart failure. Based on the severe course of the disease, we propose genetic screening for phospholamban p.Arg14del in DCM patients.

Prognostic Importance of Pulmonary Arterial Capacitance in Acute Decompensated Heart Failure With Preserved Ejection Fraction.

Background Although the prognostic importance of pulmonary arterial capacitance (PAC; stroke volume/pulmonary arterial pulse pressure) has been elucidated in heart failure with reduced ejection fraction, whether its significance in patients suffering from heart failure with preserved ejection fraction is not known. We aimed to examine the association of PAC with outcomes in inpatients with heart failure with preserved ejection fraction. Methods and Results We prospectively studied 705 patients (median age, 83 years; 55% women) registered in PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients With Heart Failure With Preserved Ejection Fraction). We investigated the association of echocardiographic PAC at discharge with the primary end point of all-cause death or heart failure rehospitalization with a mean follow-up of 384 days. We further tested the acceptability of the prognostic significance of PAC in a subgroup of patients (167/705 patients; median age, 81 years; 53% women) in whom PAC was assessed by right heart catheterization. The median echocardiographic PAC was 2.52 mL/mm Hg, with a quartile range of 1.78 to 3.32 mL/mm Hg. Univariable and multivariable Cox regression testing revealed that echocardiographic PAC was associated with the primary end point (unadjusted hazard ratio, 0.82; 95% CI, 0.72-0.92; P=0.001; adjusted hazard ratio, 0.86; 95% CI, 0.74-0.99; P=0.035, respectively). Univariable Cox regression testing revealed that PAC assessed by right heart catheterization (median calculated PAC, 2.82 mL/mm Hg) was also associated with the primary end point (unadjusted HR, 0.70; 95% CI, 0.52-0.91; P=0.005). Conclusions A prospective cohort study revealed that impaired PAC diagnosed with both echocardiography and right heart catheterization was associated with adverse outcomes in inpatients with heart failure with preserved ejection fraction. Registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024414. Unique identifier: UMIN000021831.

Renoprotection by long-term low-dose tolvaptan in patients with heart failure and hyponatremia.

AIMS: In previous randomized controlled trials, the use of tolvaptan (TLV) at a fixed dose of 30 mg/day for 1 year did not provide renal benefits in patients with heart failure (HF). This retrospective, cohort study examined the renoprotective effects of long-term, flexible-dose, and lower-dose TLV use. METHODS AND RESULTS: Tolvaptan users were defined as patients receiving TLV for at least 180 consecutive days or those who continued it until death, any cardiac events, or renal replacement therapy even if it was taken for <180 days. Of a total of 584 HF patients, 78 TLV users were identified. The median age, baseline B-type natriuretic peptide, and estimated glomerular filtration rate (eGFR) were 71 years, 243 pg/mL, and 54 mL/min/1.73 m2 , respectively. During follow-up (median, 461 days), TLV use (median average dose, 7.5 mg/day) was associated with frequent dose reductions of loop diuretics (incidence rate ratio [IRR], 1.5; 95% confidence interval [CI], 1.1-2.2), particularly in patients with serum sodium ≤135 mEq/L (IRR, 2.9; 95% CI, 1.5-5.7) (Pinteraction  = 0.04). In a mixed effects model, propensity score (PS)-matched TLV users had higher eGFRs over time than PS-matched never-users (P < 0.01). The entire cohort analyses (N = 584) yielded similar results. The renal benefit of TLV in terms of annualized eGFR slope was more pronounced in patients with lower sodium levels (Pinteraction  = 0.03). This effect modification was extinguished when patients who underwent a loop diuretic dose reduction during the follow-up period were excluded from the analysis. CONCLUSIONS: Long-term, flexible-dose, and low-dose TLV use was associated with better renal function, particularly in hyponatremic HF, possibly due to its loop diuretic dose-sparing effect in the long term.

Variability in estimated glomerular filtration rate and patients' outcomes in a real-world heart failure population.

AIMS: The prognostic significance of renal function variability has not been fully elucidated in heart failure (HF). This multicentre, prospective cohort study aimed to evaluate the usefulness of visit-to-visit variability in estimated glomerular filtration rate (eGFR) for predicting patients' outcomes in a real-world HF population. METHODS: A total of 564 patients who had survived HF hospitalization were randomly assigned with a 2:1 ratio to derivation and validation cohorts, and they were then followed after discharge. Using the data for 6 months after discharge, each patient's visit-to-visit eGFR variability (EGV) was estimated. In the derivation cohort, Cox regression analyses were performed to assess the association of EGV with a subsequent composite event (death and HF hospitalization). In the validation cohort, the predictive performance was compared among Cox regression models with EGV, those with B-type natriuretic peptide (BNP) and those with eGFR. RESULTS: In the derivation cohort (376 patients), median age, left ventricular ejection fraction (LVEF), BNP and eGFR at discharge were 72 years, 53.3%, 134.8 pg/mL and 58.7 mL/min/1.73 m2 , respectively. During a median follow-up of 2.2 years, higher EGV was associated with an increased risk of the composite event (adjusted hazard ratio [per standard deviation increase in log-transformed EGV], 1.5; 95% confidence interval, 1.1-2.0). A similar finding was observed in a stratified analysis by LVEF. In the validation cohort (188 patients), better model fit, discrimination, reclassification and calibration were observed for EGV than for 6-month averaged BNP or eGFR for predicting the composite event when added to HF risk prediction models. Adding EGV to models with BNP or eGFR improved model discrimination and reclassification. CONCLUSIONS: EGV predicts HF outcomes regardless of LVEF. Risk prediction models with EGV have good performance in real-world HF patients. The study findings highlight the clinical importance of observing visit-to-visit fluctuations in renal function in this population.

Polycythemia Vera Associated with Pulmonary Hypertension and Diffuse Large B-Cell Lymphoma: A Case Report.

BACKGROUND Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), are associated with pulmonary hypertension (PH) and malignant lymphomas. Although the underlying mechanisms have not been completely clarified, it has been suggested that the Janus kinase 2 (JAK2) mutation, which is frequently identified in PV, can be involved in the development and/or progression of these distinct diseases in patients with MPNs. However, no reports have described the coexistence of PH and malignant lymphoma in patients with MPNs. CASE REPORT A 79-year-old man being treated for PV for 27 years and PH for 5 years was hospitalized due to severe dyspnea at rest. His soluble interleukin-2 receptor levels gradually increased and the chest computed tomography showed remarkable progression of the lung lesions and an enlargement of the mediastinal and axillary lymph nodes. A lymph node biopsy was performed and the patient was diagnosed with diffuse large B-cell lymphoma (DLBCL). Owing to his poor condition, chemotherapy was not initiated, and he died on the 89th day of hospitalization. The pathological autopsy revealed the destruction of alveolar structures with neoplastic space-occupying lesions of DLBCL. Multifactorial features of PH associated with MPNs, including the intimal thickening of pulmonary arteries accompanied by megakaryocytes and obstructed pulmonary arteries with organized thrombi in the lung tissue specimens, were observed. We found a JAK2 mutation based on a genetic analysis of the patient's bone marrow. CONCLUSIONS We present the rare case of a patient who had PV with a JAK2 mutation, which coexisted with PH and DLBCL, and he developed severe refractory respiratory failure.

Phenotypic recapitulation and correction of desmoglein-2-deficient cardiomyopathy using human-induced pluripotent stem cell-derived cardiomyocytes.

Desmoglein-2, encoded by DSG2, is one of the desmosome proteins that maintain the structural integrity of tissues, including heart. Genetic mutations in DSG2 cause arrhythmogenic cardiomyopathy, mainly in an autosomal dominant manner. Here, we identified a homozygous stop-gain mutations in DSG2 (c.C355T, p.R119X) that led to complete desmoglein-2 deficiency in a patient with severe biventricular heart failure. Histological analysis revealed abnormal deposition of desmosome proteins, disrupted intercalated disk structures in the myocardium. Induced pluripotent stem cells (iPSCs) were generated from the patient (R119X-iPSC), and the mutated DSG2 gene locus was heterozygously corrected to a normal allele via homology-directed repair (HDR-iPSC). Both isogenic iPSCs were differentiated into cardiomyocytes [induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)]. Multielectrode array analysis detected abnormal excitation in R119X-iPSC-CMs but not in HDR-iPSC-CMs. Micro-force testing of three-dimensional self-organized tissue rings (SOTRs) revealed tissue fragility and a weak maximum force in SOTRs from R119X-iPSC-CMs. Notably, these phenotypes were significantly recovered in HDR-iPSC-CMs. Myocardial fiber structures in R119X-iPSC-CMs were severely aberrant, and electron microscopic analysis confirmed that desmosomes were disrupted in these cells. Unexpectedly, the absence of desmoglein-2 in R119X-iPSC-CMs led to decreased expression of desmocollin-2 but no other desmosome proteins. Adeno-associated virus-mediated replacement of DSG2 significantly recovered the contraction force in SOTRs generated from R119X-iPSC-CMs. Our findings confirm the presence of a desmoglein-2-deficient cardiomyopathy among clinically diagnosed dilated cardiomyopathies. Recapitulation and correction of the disease phenotype using iPSC-CMs provide evidence to support the development of precision medicine and the proof of concept for gene replacement therapy for this cardiomyopathy.

The Effect of a Cancer History on Patients with Acute Myocardial Infarction After Percutaneous Coronary Intervention.

The effect of a history of cancer on the prognosis of patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) is poorly understood.From the Osaka Acute Coronary Insufficiency Study (OACIS) registry in Osaka, Japan, we enrolled the case data of a total of 3499 patients with AMI treated with PCI between 1998 and 2014, of whom 462 had a cancer history (cancer group, 13.2%) and 3037 did not (non-cancer group, 86.8%). All of the cases were followed for up to five years from discharge.The Kaplan-Meier curve and multivariate analysis using Cox proportional hazards models revealed that all-cause mortality was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR], 2.43; P < 0.001). Deaths from cardiac, cancer, and other causes were treated as competing events, and competing analysis using the cumulative incidence function (CIF) and Fine-Gray model revealed that mortality due to cancer was higher in the cancer group than in the non-cancer group, whereas cardiac mortality was similar between the two groups. The incidences of cardiovascular events, including stroke, recurrent infarction, and heart failure requiring readmission, were also similar between the two groups, although the Kaplan-Meier analysis and univariate Cox proportional hazards model revealed that the incidence of stroke was higher in the cancer group than in the non-cancer group.A history of cancer increased all-cause and cancer mortality among patients with AMI treated with PCI, although it was not associated with cardiovascular events.

Multiple percutaneous coronary interventions worsen outcomes for subsequent surgical correction of chronic ischemic mitral regurgitation.

Objective: We investigated whether or not a history of multiple percutaneous coronary interventions (PCIs) is associated with clinical outcomes after surgery for ischemic mitral regurgitation. Methods: A total of 309 patients with chronic ischemic mitral regurgitation and left ventricular ejection fraction ≤40% who underwent restrictive mitral annuloplasty were classified as follows: patients with no or 1 previous PCI (nonmultiple PCI group [n = 211]) and patients with 2 or more previous PCIs (multiple PCIs group [n = 98]). Mean follow-up duration was 53 ± 40 months. Results: Before surgery, there were no intergroup differences in patient demographic characteristics except for lower estimated glomerular filtration rate in patients with multiple PCIs. These patients underwent concomitant coronary artery bypass grafting less frequently with a lower number of distal anastomoses (P < .05 for both). The 30-day mortality was 3.3% and 2.0% in the nonmultiple and multiple PCIs group, respectively (P = .72). During follow-up, there were 157 deaths. Patients with multiple PCIs showed lower 5-year survival rate (44% vs 64%; P = .002). After adjustments with inverse-probability-of-treatment weighting, multiple PCIs history was an independent risk factor for mortality (adjusted hazard ratio, 1.4; 95% confidential interval, 1.1-1.7; P = .002). Patients with multiple PCIs showed less improvement in left ventricular ejection fraction (interaction effect P < .001). Conclusions: In patients with ischemic mitral regurgitation, a history of previous multiple PCIs was associated with increased risk of long-term postoperative mortality, with less improvement in left ventricular ejection fraction.

Adeno-associated virus-mediated gene delivery promotes S-phase entry-independent precise targeted integration in cardiomyocytes.

Post-mitotic cardiomyocytes have been considered to be non-permissive to precise targeted integration including homology-directed repair (HDR) after CRISPR/Cas9 genome editing. Here, we demonstrate that direct delivery of large amounts of transgene encoding guide RNA (gRNA) and repair template DNA via intra-ventricular injection of adeno-associated virus (AAV) promotes precise targeted genome replacement in adult murine cardiomyocytes expressing Cas9. Neither systemic injection of AAV nor direct injection of adenovirus promotes targeted integration, suggesting that high copy numbers of single-stranded transgenes are required in cardiomyocytes. Notably, AAV-mediated targeted integration in cardiomyocytes both in vitro and in vivo depends on the Fanconi anemia pathway, a key component of the single-strand template repair mechanism. In human cardiomyocytes differentiated from induced pluripotent stem cells, AAV-mediated targeted integration fluorescently labeled Mlc2v protein after differentiation, independently of DNA synthesis, and enabled real-time detection of sarcomere contraction in monolayered beating cardiomyocytes. Our findings provide a wide range of applications for targeted genome replacement in non-dividing cardiomyocytes.

Diagnostic performance of coronary angiography utilizing intraprocedural 320-row computed tomography with minimal contrast medium.

Recently developed coronary angiography with intraprocedural 320-row computed tomography can be performed in a catheterization laboratory (XACT) by injecting contrast medium from a place close to the coronary arteries, thereby requiring a minimal amount of contrast medium. However, its clinical application has not yet been established. This study aimed to evaluate the diagnostic accuracy of XACT angiography with a minimal volume of contrast medium in patients with suspected coronary artery disease (CAD). A total of 167 coronary segments were analyzed in 14 patients (9 males, median age 70 years) with suspected CAD by XACT angiography with 7.5 ml of contrast medium and invasive coronary angiography (ICA) with standard techniques. The segmental-based diagnostic accuracy of XACT angiography in detecting stenosis of ≥ 50% and ≥ 75% and visualized by ICA was good (sensitivity: 74% and 62%, specificity: 99% and 99%, positive predictive value: 93% and 80%, and negative predictive value: 97% and 97%, respectively). These results suggest that XACT angiography with a very low amount of contrast medium may have strong clinical utility for screening coronary arteries in patients with renal dysfunction or undergoing clinical procedures such as pacemaker implantation.