Vaccines are well-known therapies for infectious disease and cancer; however, recently, we and others have developed vaccines for other chronic diseases, such as hypertension, diabetes and dyslipidemia. Although we have many treatment options for hypertension, including angiotensin II type 1 receptor blockers, calcium-channel blockers, and diuretics, a substantial portion of the hypertensive population has uncontrolled blood pressure due to poor medication adherence. When these vaccines are established in the future as therapeutic options for chronic diseases, their administration regimen, such as several times per year, will replace daily medication use. Thus, therapeutic vaccines might be a novel option to control the progression of cardiovascular diseases. Importantly, regarding the development of vaccines against self-antigens (i.e., angiotensin II), the vaccine should efficiently induce a blocking antibody response against the self-antigen without provoking cytotoxic T cells. Therefore, to address the safety and efficiency of therapeutic vaccines, we have developed an original B-cell vaccine to induce antibody production and used carrier proteins, which include exogenous T-cell epitopes through the major histocompatibility complex. In this review, we will introduce the challenges in developing therapeutic vaccines for chronic diseases and describe the therapeutic potential for cardiovascular diseases.
The elderly population is increasing because of increasing life expectancy, and the prevalence of frailty increases with age. Frailty commonly coexists with cardiovascular diseases (CVDs), such as coronary artery disease (CAD), heart failure (HF), aortic stenosis (AS), and atrial fibrillation (AF). Frail patients who undergo revascularization for CAD have higher complication rates; those with HF have a high prevalence of poor outcomes, and those with AF are vulnerable to increased stroke incidence. Moreover, frailty and asymptomatic severe AS were independent factors for mortality. The presence of frailty can lead to poor clinical outcomes, and frailty has been identified as a risk factor for mortality. Thus, the identification of frail patients who are at higher risks of disability and adverse clinical outcomes is important. In this review, the relationship between frailty and CVD is appraised and optimal treatments for frail patients are discussed.
Background:There is insufficient real-world data on the current status of Japanese patients with venous thromboembolism (VTE) or its treatment and prevention with rivaroxaban.
Methods and Results:In this multicenter, prospective, observational study conducted in Japan, 1,039 patients with acute symptomatic/asymptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) with or without DVT prescribed rivaroxaban were enrolled at 152 institutions and observed for a median of 21.3 months. Mean age was 68.0±14.7 years, mean body weight was 60.3±14.1 kg, 59.0% were females, and 19.0% had active cancer. Incidences of recurrence or aggravation of symptomatic VTE (primary effectiveness outcome) and major bleeding (principal safety outcome) were 2.6% and 2.9% per patient-year, respectively. These outcomes did not differ between patients with DVT and those with PE (primary effectiveness outcome: 2.6% vs. 2.5% per patient-year, P=0.810; principal safety outcome: 3.5% vs. 2.4% per patient-year, P=0.394). The incidence of composite clinically relevant events, including recurrence or aggravation of symptomatic VTE, acute coronary syndrome, ischemic stroke, all-cause death, or major bleeding events, was 9.2% per patient-year. Multivariate analysis revealed that male sex, being underweight, having active cancer, chronic heart and lung disease, and previous stroke were independent determinants for composite clinically relevant events.
Conclusions:In Japanese clinical practice, a single-drug approach with rivaroxaban was demonstrated to be a valuable treatment for a broad range of VTE patients.
Background:The effect of remote monitoring (RM) in atrial arrhythmia detection, stroke reduction, and anticoagulation therapy remains unknown, particularly for patients with implantable or wearable cardiac devices.
Methods and Results:We performed a systematic review and meta-analysis to evaluate the role of RM in atrial arrhythmia detection, stroke reduction and anticoagulation therapeutic intervention. Online databases were queried to include randomized controlled trials comparing detection of atrial arrhythmia and stroke risk between patients undergoing RM and those receiving in-office (IO) follow-up. Outcomes and complications of RM-guided anticoagulation therapy and conventional therapy in patients with atrial fibrillation were also reviewed. A total of 16 studies were included. Compared with patients receiving IO follow-up, patients undergoing RM had a significantly higher detection rate of atrial arrhythmia (risk ratio [RR], 1.363; 95% confidence interval [CI], 1.147–1.619), and a lower risk of stroke (RR, 0.539; 95% CI, 0.301–0.936). The higher rate of atrial arrhythmia was only noted in patients with wearable devices (RR, 4.070; 95% CI, 2.408–6.877), and the lower risk of stroke was only noted in patients with cardiovascular implantable electronic devices (CIED) (RR, 0.513; 95% CI, 0.265–0.996).
Conclusions:RM is effective for atrial arrhythmia detection in patients using wearable devices and for reducing the risk of stroke in patients with CIED.
Background:The association between binge alcohol ingestion and atrial fibrillation (AF), often termed “holiday heart syndrome”, has long been recognized. However, the underlying cellular and molecular mechanisms are unknown.
Methods and Results:An experimental model of binge alcohol-induced AF was developed to elucidate the mechanisms linking acute ethanol exposure to changes in ion channel transcription and AF susceptibility. AF-susceptibility during transesophageal electrical stimulation was enhanced 8 h after, but not immediately or 24 h after, acute alcohol intake. T-type calcium channel (TCC) blockade and calcineurin inhibition diminished the AF-promoting effect of ethanol. Long-term (8–24 h) exposure to ethanol augmented TCC isoform-expression (Cav3.1 and Cav3.2) and currents in cardiomyocytes, accompanied by upregulation of the transcription factors, Csx/Nkx2.5 and nuclear factor of activated T-cells (NFAT), in the nucleus, and of phospho-glycogen synthesis kinase 3β (GSK3β) in the cytosol. Inhibition of protein kinase C (PKC) during the 7- to 8-h period following ethanol exposure attenuated susceptibility to AF, whereas acute exposure did not. GSK3β inhibition itself upregulated TCC expression and increased AF susceptibility.
Conclusions:The present study results suggest a crucial role for TCC upregulation in the AF substrate following binge alcohol-drinking, resulting from ethanol-induced PKC-activation that hyperphosphorylates GSK3β to cause enhanced calcineurin-NFAT-Csx/Nkx2.5 signaling. These observations elucidate for the first time the potential mechanisms underlying the clinically well-recognized, but mechanistically enigmatic, “holiday heart syndrome”.
Background:Second-generation drug-eluting stents (DES) reduce the incidence of stent thrombosis, even in patients with ST-segment elevated myocardial infarction (STEMI). However, the early local vascular healing after DES implantation in STEMI lesions, which mainly concerns stent thrombosis, is still unclear.
Methods and Results:We attempted to determine early local vascular healing 3 months after cobalt–chromium everolimus-eluting stent (CoCr-EES) implantation in STEMI lesions relative to stable coronary artery disease (CAD) lesions. This prospective, multicenter study analyzed 96 total lesions (STEMI=49, stable CAD=51) by frequency domain-optical coherence tomography (FD-OCT) performed post-procedure and at the 3-month follow-up. Although CoCr-EES implanted in STEMI were almost entirely covered at 3 months, they had a relatively high incidence of uncovered struts compared with stable CAD (5.5% vs. 1.6%, P<0.001). Intrastent thrombus in the 2 groups was primarily resolved at the 3-month follow-up (STEMI: 91.7%→26.5%, stable CAD: 74.5%→11.8%). Regarding irregular protrusion, complete resolution was observed in stable CAD (21.6%→0%), while a few stents remained in STEMI (79.2%→8.2%). Although there were almost no changes for the serial change of average lumen area in STEMI, there were slight but significant decreases in stable CAD [STEMI 0.08 (−0.44, 0.55) mm2, stable CAD −0.35 (−0.55, 0.11) mm2; P=0.009].
Conclusions:Although strut coverage after CoCr-EES implantation for STEMI lesions was slightly delayed, the healing process appeared to be acceptable in both STEMI and stable CAD.
Background:Continuous-flow left ventricular assist device (CF-LVAD) substantially improves survival in endstage heart failure patients. However, bleeding complications are common after CF-LVAD implantation and in some cases, re-exploration for bleeding is needed. We aimed to investigate the incidence, timing, and risk factors of bleeding requiring re-exploration after CF-LVAD implantation.
Methods and Results:We retrospectively reviewed 162 consecutive patients (age 43±13 years, 71% men) who underwent CF-LVAD implantation (HeartMateII 119, Jarvik2000 15, HVAD 13, EVAHEART 10, DuraHeart 5) from January 2012 to June 2019. During follow-up [median 662 days, interquartile range (IQR) 364–1,116 days], 35 (21.6%) experienced re-exploration for bleeding. The median timing of re-exploration was 6 (IQR 1–10) days. In the multivariate logistic regression analysis, postoperative platelet count was an independent predictor for re-exploration for bleeding after CF-LVAD implantation (per 104/μL: odds ratio 0.83, 95% confidence interval 0.74–0.93, P=0.002). Patients who experienced re-exploration for bleeding had a significantly worse survival rate than patients who did not (at 4 years, 73.6% vs. 90.1%, P=0.039).
Conclusions:Re-exploration for bleeding is prevalent after CF-LVAD implantation, especially in patients with low postoperative platelet counts. As bleeding requiring re-exploration is associated with poor prognosis, risk stratification using the postoperative platelet count may be beneficial for these patients.
Background:Recent progress in chemotherapy has prolonged the survival of patients with hematological diseases, but has also increased the number of patients with chemotherapy-related cardiac dysfunction (CTRCD). However, the causes of individual variations and risk factors for CTRCD have yet to be fully elucidated.
Methods and Results:Consecutive echocardiograms of 371 patients were retrospectively evaluated for the presence of left ventricular (LV) non-compaction (LVNC). Individual LV ejection fraction (LVEF) outcome estimates were made using bivariate linear regression with log-transformed duration Akaike information criterion (AIC) model fitting. The prevalence of LVNC was 6-fold higher in patients with hematological diseases than in those with non-hematological diseases (12% vs. 2%; risk ratio 6.1; 95% confidence interval [CI] 2.0, 18.2). Among patients with hematological diseases, the ratio of myeloid diseases was significantly higher in the group with LVNC (P=0.031). Deterioration of LVEF was more severe in patients with than without LVNC (–14.4 percentage points/year [95% CI –21.0, –7.9] vs. –4.6 percentage points/year [95% CI –6.8, –2.4], respectively), even after multivariate adjustment for baseline LVEF, background disease distributions, cumulative anthracycline dose, and other baseline factors.
Conclusions:LVNC is relatively prevalent in patients with hematological diseases (particularly myeloid diseases) and can be one of the major risk factors for CTRCD. Detailed cardiac evaluations including LVNC are recommended for patients undergoing chemotherapy.
Background:The early mitral inflow velocity to mitral early diastolic velocity ratio (E/e′) and electrocardiogram (ECG) determination of QRS score are useful for risk stratification in patients with ST-elevation myocardial infarction (STEMI).
Methods and Results:In this study, 420 consecutive patients (357 male; mean [±SD] age 63.6±12.2 years) with first-time STEMI who successfully underwent primary percutaneous coronary intervention within 12 h of symptom onset were followed-up for 5 years (median follow-up 67 months). Echocardiography, ECG, and blood samples were obtained 2 weeks after onset. Infarct size was estimated by the QRS score after 2 weeks (QRS-2wks) and creatine phosphokinase-MB concentrations (peak and area under the curve). The primary endpoint was death from cardiac causes or rehospitalization for heart failure (HF). During follow-up, 21 patients died of cardiac causes and 62 had HF. Multivariate Cox proportional hazard analysis showed that mean E/e′ (hazard ratio [HR] 1.152; 95% confidence interval [CI] 1.088–1.215; P<0.0001), QRS-2wks (HR 1.153; 95% CI 1.057–1.254; P<0.0001), and hypertension (HR 1.702; 95% CI 1.040–2.888; P=0.03) were independent predictors of the primary endpoint. Kaplan-Meier curve analysis showed that patients with QRS-2wks >4 and mean E/e′ >14 were at an extremely high risk of cardiac death or HF (log rank, χ2=116.3, P<0.0001).
Conclusions:In patients with STEMI, a combination of QRS-2wks and mean E/e′ was a simple but useful predictor of cardiac death and HF.
Background:Risk stratification of patients with non-ST-segment elevation myocardial infarction (NSTEMI) is important in terms of treatment strategy selection. Current efforts have focused on short-term risk prediction after discharge, but we aimed to establish a risk score to predict the 24-month mortality risk in survivors of NSTEMI.
Methods and Results:A total of 5,509 patients diagnosed with NSTEMI between January 2013 and September 2014 were included. Primary endpoint was all-cause death at 24 months. A multivariable Cox regression model was used to establish a practical risk score based on independent risk factors of death. The risk score included 9 variables: age, body mass index, left ventricular ejection fraction, reperfusion therapy during hospitalization, Killip classification, prescription of diuretics at discharge, heart rate, and hemoglobin and creatinine levels. The C-statistics for the risk model were 0.83 (95% confidence interval [CI]: 0.81–0.85) and 0.83 (95% CI: 0.79–0.86) in the development and validation cohorts, respectively. Mortality risk increased significantly across groups: 1.34% in the low-risk group (score: 0–58), 5.40% in intermediate group (score: 59–93), and 23.87% in high-risk group (score: ≥94).
Conclusions:The current study established and validated a practical risk score based on 9 variables to predict 24-month mortality risk in patients who survive NSTEMI. This score could help identify patients who are at high risk for future adverse events who may benefit from good adherence to guideline-recommended secondary prevention treatment.
Background:PRASFIT-Practice II is a postmarketing observational study conducted in 4,155 Japanese patients with ischemic heart disease (IHD) who received long-term prasugrel. The data were used to assess the utility of Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria.
Methods and Results:Patients in PRASFIT-practice II were clinically followed for 2 years. The primary endpoint was the cumulative incidence of major adverse cardiovascular events (MACE) and Thrombolysis in Myocardial Infarction (TIMI) major/minor bleeding. Patients were divided into 2 groups based on ARC-HBR criteria (HBR (40.1% of patients) and non-HBR (59.9%)) and the effect of HBR on the primary endpoint was assessed. The median duration of dual antiplatelet therapy with prasugrel was 391.0 days. At 2 years, the cumulative incidence of MACE was 3.3%, and of TIMI major/minor bleeding was 2.7%. At 1 year, MACE and TIMI major/minor bleeding in the HBR group (4.0% and 3.4%, respectively) were higher than that in the non-HBR group (1.3% for both). Landmark analysis at 3 months and 1 year showed that the higher risk of MACE or TIMI major/minor bleeding in the HBR group persisted through 2 years.
Conclusions:The results of this study confirmed the safety and effectiveness of long-term treatment with prasugrel, and demonstrated that the ARC-HBR criteria for bleeding risk are applicable in Japanese IHD patients treated with prasugrel.
Background:Duplex ultrasound scanning (DUS) plays a major role in less invasive diagnosis and assessment of lesion severity in lower extremity peripheral artery disease (PAD). In this study, we evaluated the efficacy of each DUS parameter measured in patients with PAD and established a simple method for PAD evaluation.
Methods and Results:We retrospectively investigated 211 patients (270 limbs) who underwent assessment with both angiography and DUS. During DUS of the common femoral artery (CFA) and popliteal artery, we measured 3 parameters: acceleration time (AcT), peak systolic velocity (PSV), and waveform contour. We compared these parameters with the degree of angiographic stenosis. AcT at the CFA had a significantly higher value in prediction of aortoiliac artery lesions with >50% stenosis (c-index, 0.85; 95% confidence interval (CI), 0.79–0.91), with a sensitivity of 0.82 and specificity of 0.76 at the best cutoff point, compared with PSV and waveform contour (P<0.001, respectively). For femoropopliteal lesions, the ratio of AcT at the popliteal artery to AcT at the CFA is the most predictive parameter, with sensitivity of 0.86 and specificity of 0.92 at the best cutoff point (c-index, 0.93; 95% CI, 0.90–0.97), compared with others (P<0.001, respectively).
Conclusions:For the assessment of PAD with DUS, AcT and AcT ratio are simple and reliable parameters for evaluating aortoiliac and femoropopliteal artery disease.
Background:The detailed mechanism of early-phase arterial healing after novel fluoropolymer-based paclitaxel-eluting stent (PES) implantation in the femoropopliteal (FP) lesions has not been elucidated.
Methods and Results:We evaluated the intravascular status of 20 PES implanted in 11 FP lesions of 9 patients using angioscopy at approximately 3 months after implantation. Angioscopic images were analyzed to determine (1) the dominant degree of neointimal coverage (NIC) over the stent; (2) the extent of uncovered struts; and (3) the presence of intrastent thrombus. NIC was classified into 4 grades: grade 0, stent struts fully visible; grade 1, stent struts bulging into the lumen although covered; grade 2, stent struts embedded in neointima, but translucently visible; grade 3, stent struts fully embedded and invisible. The extent of uncovered struts was scored as follows: score 0, no uncovered struts of the entire stent; score 1, uncovered struts area approximately <30% of the stent; and score 2, uncovered struts area approximately ≥30% of the stent. In total, 90% of stents demonstrated grade 1 dominant NIC and 10% showed grade 2 dominant NIC; 85% of stents showed an uncovered stent score of 0, and the remainder had a score of 1. Thrombus was observed in all stents.
Conclusions:Widely uncovered stent struts were not observed by angioscopy at 3 months after PES implantation in these FP lesions, even with the detection of thrombus adhesion.
Background:Patients with cancer-associated venous thromboembolism (VTE) are at high risk for recurrent VTE and are recommended to receive prolonged anticoagulation therapy if they are at a low risk for bleeding. However, there are no established risk factors for bleeding during anticoagulation therapy.
Methods and Results:The COMMAND VTE Registry is a multicenter retrospective registry enrolling 3,027 consecutive patients with acute symptomatic VTE among 29 Japanese centers. The present study population consisted of 592 cancer-associated VTE patients with anticoagulation therapy. We constructed a multivariable Cox proportional hazard model to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the potential risk factors for major bleeding. During a median follow-up period of 199 days, major bleeding occurred in 72 patients. The cumulative incidence of major bleeding was 5.8% at 3 months, 13.8% at 1 year, 17.5% at 2 years, and 28.1% at 5 years. The most frequent major bleeding site was gastrointestinal tract (47%). Terminal cancer (adjusted HR, 4.17; 95% CI, 2.22–7.85, P<0.001), chronic kidney disease (adjusted HR, 1.89; 95% CI 1.06–3.37, P=0.031), and gastrointestinal cancer (adjusted HR, 1.78; 95% CI, 1.04–3.04, P=0.037) were independently associated with an increased risk of major bleeding.
Conclusions:Major bleeding events were common during anticoagulation therapy in real-world cancer-associated VTE patients. Terminal cancer, chronic kidney disease, and gastrointestinal cancer were the independent risk factors for major bleeding.
Background:Asian patients have smaller aortic annuli. Although 20-mm balloon-expandable (BE) transcatheter heart valves (THV) are manufactured for transcatheter aortic valve implantation (TAVI) in these cases, the supra-annular design of self-expandable (SE) THV is considered more suitable; however, real-world comparative data are scarce.
Methods and Results:Consecutive TAVI cases (n=330) in a single Japanese center were reviewed. Based on the cutoff for the new-generation 20-/23-mm BE-THV, a small aortic annulus was defined as <330 mm2. A considerable number of patients had small annuli: 49/302 (16%). Of these, 33 BE-THV and 13 SE-THV using new-generation valves were compared. Although the SE-THV group had smaller annulus area (median 297 (interquartile range, 280–313) vs. 309 (303–323) mm2(P=0.022)), it had more favorable post-procedural parameters; for SE-THV and BE-THV, respectively, effective orifice area (EOA), 1.5 (1.3–1.6) vs. 1.1 cm2(0.9–1.3) (P=0.002); mean pressure gradient, 7.6 (5.6–11.0) vs. 14.2 mmHg (11.2–18.8) (P=0.001); and peak velocity, 1.8 (1.6–2.4) vs. 2.7 m/s (2.3–3.1) (P=0.001). Although new left bundle branch block was higher with SE-THV (24% and 62%, P=0.02), patient-prosthesis mismatch (PPM) ≥ moderate (indexed EOA <0.85 cm2/m2) was significantly less with SE-THV than with BE-THV (8% vs. 55%; P=0.04). Hemodynamic findings were consistent up to 1 year.
Conclusions:Small annuli are often seen in Asian patients, for whom SE-THV implantation results in favorable hemodynamics with less PPM.
Background:The Japanese Circulation Society proposes recommendations for all healthcare professionals involved in cardiovascular medicine to protect them from infection and ensure that seriously ill patients requiring urgent care receive proper treatment.
Methods and Results:Patients are divided into “Positive or suspected coronavirus disease 2019 (COVID-19)” and “All others”. Furthermore, tests and treatments are divided into emergency or standby. For each category, we propose recommendations.
Conclusions:To maintain the cardiovascular care system, The Japanese Circulation Society recommends completely preventing nosocomial COVID-19 infections, ensuring adequate PPE necessary for healthcare personnel, and learning and implementing standard precautions.
Background:SARS-CoV-2 infection is associated with myocardial injury, but there is a paucity of experimental platforms for the condition.
Methods and Results:Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected by SARS-CoV-2 for 3 days ceased beating and exhibited cytopathogenic changes with reduced viability. Active viral replication was evidenced by an increase in supernatant SARS-CoV-2 and the presence of SARS-CoV-2 nucleocaspid protein within hiPSC-CMs. Expressions of BNP, CXCL1, CXCL2, IL-6, IL-8 and TNF-α were upregulated, while ACE2 was downregulated.
Conclusions:Our hiPSC-CM-based in-vitro SARS-CoV-2 myocarditis model recapitulated the cytopathogenic effects and cytokine/chemokine response. It could be exploited as a drug screening platform.