Chronic kidney disease (CKD) is a global health problem. CKD patients are at high risk of developing cardiovascular disease (CVD), including coronary artery disease, heart failure and stroke. Several factors invoke a vicious cycle of CKD and CVD, which is referred as to “cardiorenal syndrome”. Among these factors, the compounds retained through loss of renal excretion play a pathological role in causing atherosclerosis and CVD. These compounds have been broadly classified as uremic toxins because of their accumulation with declining renal function and cytotoxicity. The major uremic toxins contributing to CVD are asymmetric dimethylarginine (ADMA), advanced glycation endproducts (AGE), and trimethyl amine N-oxide (TMAO). ADMA is linked to CVD through regulation of nitric oxide, reactive oxygen species, and renal anemia. AGE not only directly accumulates in the heart and kidney, but interacts with the receptor for AGE (RAGE), leading to cell damage in CVD. TMAO correlates with a high prevalence of CVD and promotes organ fibrosis by itself. The levels of these and other uremic toxins rise with worsening CKD, inducing multiplicative damage in the heart and kidney. Therefore, a better understanding of uremic toxins has great clinical importance for preventing cardiorenal syndrome. This review highlights the molecular mechanism by which these uremic toxins are implicated in CVD and suggests the possible mutual relationship between them.

Transthyretin cardiac amyloidosis is a progressive and life-threating disease that is significantly underdiagnosed, and the actual number of patients with the disease is presently unknown. Accumulation of wild-type transthyretin-derived amyloid in the heart is a common finding in very elderly patients. Recent clinical trials demonstrated that tafamidis reduced all-cause death and the number of cardiovascular hospitalizations when compared with placebo. The Japanese Ministry of Health, Labour and Welfare approved tafamidis (Vyndaqel^®, Pfizer Inc.) for the treatment of cardiomyopathy caused by both wild-type and mutated transthyretin-derived amyloidoses. This scientific statement on transthyretin-derived cardiac amyloidosis summarizes the conditions for reimbursement of the cost of tafamidis therapy, and the institutional and physician requirements for the introduction of tafamidis.

Background:Cardiac resynchronization therapy (CRT) is less effective in patients with mildly wide QRS or non-left bundle branch block (non-LBBB). A new algorithm of every minute’s optimization (adaptive CRT: aCRT algorithm) is effective in patients with CRT devices. This study investigated the clinical effect of the aCRT algorithm, especially in mildly wide QRS (120≤QRS<150 ms) or non-LBBB patients receiving CRT.

Methods and Results:This study included 104 CRT patients (48 patients using the aCRT algorithm [adaptive group] and 56 patients not using the aCRT algorithm [non-adaptive group]). The primary endpoint was a composite clinical outcome of cardiac death and/or heart failure (HF) hospitalization. During a median follow-up of 700 days (interquartile range 362–1,173 days), aCRT reduced the risk of the clinical outcome, even in patients with mildly wide QRS or non-LBBB (log-rank P=0.0030 and P=0.0077, respectively) by Kaplan-Meier analysis. Use of the aCRT algorithm was an independent predictor of clinical outcomes in the multivariate analysis (hazard ratio (HR) 0.28, 95% confidence interval (CI): 0.096–0.78, P=0.015), the same as in patients with mildly wide QRS (HR 0.12, 95% CI: 0.006–0.69, P=0.015).

Conclusions:The new aCRT algorithm was useful and significantly reduced the risk of the clinical outcome, even in patients with mildly wide QRS.

Background:Because premature ventricular contractions (PVCs) are one of the most common arrhythmias, but with unclear causative mechanisms, we studied the hemodynamic features that can cause symptomatic PVCs.

Methods and Results:We studied 109 patients (48 males, age 60±19 years) with frequent monomorphic PVCs and no structural heart disease. The left ventricular inflow diastolic filling velocity was recorded by transthoracic echocardiography (TTE) at the time of PVCs in all patients. We assessed the PVC E wave flow (E wave velocity×duration at PVC). A total of 38 patients (35%) had PVC-related symptoms (19 palpitations, 12 pulse deficit, 6 shortness of breath, 6 malaise, 1 syncope). These patients showed reduced PVC E wave flow (9.3±6.0 vs. 14.6±6.5 cm, P<0.0001), and reduced PVC stroke volume (20.5±10.8 vs. 29.9±17.2 mL, P=0.0030). In the multivariate analysis, only reduced PVC E wave flow was independently associated with PVC-related symptoms (P=0.00349, odds ratio: 1.134029, each 1.0 cm increase in PVC E wave flow, 95% confidence interval: 1.040726–1.247544).

Conclusions:Decreased E wave flow at the time of PVC was independently related with PVC-related symptoms in patients with PVCs. The LV contraction at the time of inadequate filling might be a cause of PVC-related symptoms.

Background:We investigated for the first time the suitability of landiolol, an ultra-short-acting β1-specific β-blocker, for the treatment of atrial fibrillation/atrial flutter (AF/AFL) in Caucasian patients.

Methods and Results:The 20 study patients received landiolol as a continuous infusion (starting dose 40 µg/kg/min) with (B+CI) or without (CI) a preceding bolus dose (100 µg/kg/min administered over 1 min) in a prospective open-label study. The primary endpoint was the proportion of patients with sustained heart rate (HR) reduction ≥20% or to <90 beats/min within 16 min of starting the CI. Secondary endpoints were the pharmacodynamics, pharmacokinetics, AF/AFL symptoms, safety and tolerability of landiolol. At 16 min, HR was reduced in all patients treated with landiolol. The primary endpoint was met by 60% of patients in the CI group and 40% in the B+CI group without a significant group difference. Overall reduction of AF/AFL symptoms at 16 min was 72%. Safety and local tolerability of landiolol were excellent, and no serious adverse events occurred.

Conclusions:Continuous infusion of landiolol with a starting dose of 40 µg/kg/min is suitable for the acute treatment of tachycardic AF/AFL in Caucasian patients. Administration of a preceding bolus seems unnecessary.

Background:The incidence and short- and long-term outcomes of coronary artery perforation (CAP) are not well described.

Methods and Results:We analyzed the characteristics and the short- and long-term outcomes of CAP among 243,149 patients undergoing percutaneous coronary interventions (PCI) from 2005 until 2017 in the national Swedish registry. We identified 1,008 cases of CAP with an incidence of 0.42%. Major adverse event rates were significantly higher in patients with CAP than non-CAP (P<0.001). The 1-year mortality rate was 16% vs. 5.5%, respectively, and the 12-year mortality rate was 52% vs. 34%. The restenosis rate was 5.2% vs. 3.1% and 17% vs. 9%, respectively. The target lesion revascularization rate was 4.2% vs. 2.6% and 10.5% vs. 7%. The stent thrombosis rate was numerically higher, 1.5% vs. 0.8% and 4.5 vs. 2.8%, with no stent thrombosis cases for equine pericardial stent grafts. Among the patients with tamponade a large proportion of cases occurred at the late stage (215/1,008, 21%), and most were not recognized in the cath-lab (167/215, 78%). The mortality rate for late tamponade was similar in patients suffering acute tamponade at 1 year (25.6% vs. 27%) or at 12 years (54% vs. 58%).

Conclusions:CAP is associated with an early high excess in morbidity and mortality but with low risk of additional adverse events in the long term. Late tamponade is as deadly as acute tamponade.

Background:Stroke is a major concern in minimally invasive cardiac surgery, so we investigated the incidence and risk factors of cerebral embolism according to the systemic perfusion strategy under thorough imaging assessment.

Methods and Results:Between November 2011 and May 2015, 315 cardiac surgery patients who underwent preoperative computed tomography angiography (CTA) as a routine evaluation were enrolled. The incidence and distribution of cerebral embolism were analyzed with routine postoperative brain diffusion-weighted magnetic resonance imaging (DW-MRI) examination. Anterograde perfusion was used in 103 patients (group A), and retrograde perfusion was performed in 212 patients (group R). Operative deaths, incidence of clinical stroke (group A: 0%, group R: 0.5%, P=0.77), and rate of cerebral embolism (group A: 35.9%, group R: 26.4%, P=0.08) were comparable. The median number of new embolic lesions detected by MRI per patient (group A: 2, group R: 2, P=0.16), maximal diameter of the lesion (group A: 6.5 mm, group R: 6.0 mm, P=0.97), and anatomic distribution of the lesion were similar between groups. In the multivariate analysis, hypertension, emergency status, atherosclerosis grade 3 or 4 (intimal thickening >4 mm), and cardiopulmonary bypass time were independent risk factors for postoperative cerebral embolism, but retrograde perfusion was not.

Conclusions:According to the results of postoperative DW-MRI, retrograde perfusion itself might not increase the incidence of postoperative cerebral embolism in properly selected cardiac surgery patients undergoing routine preoperative CTA examination.

Background:Size-mismatched heart transplantation (HTx) is associated with a risk of stenosis of the caval anastomosis site or low cardiac output syndrome. We developed a modified bicaval anastomosis technique (mBCAT) that achieved an adjustable caval anastomosis to compensate for size mismatch. This study was performed to validate the rationale of the mBCAT for size-mismatched HTx.

Methods and Results:This institutional consecutive series involved 106 patients who underwent HTx with the mBCAT during an 18-year period. The cohort was divided into 3 groups according to the donor-to-recipient body weight ratio: <0.8, undersized group (n=17); 0.8–1.3, size-matched group (n=68); and >1.3, oversized group (n=21); outcomes were compared. The undersized, size-matched, and oversized groups showed no significant differences in the rate of mild or worse echocardiographic tricuspid regurgitation at 1 month [1 (5.8%), 7 (10.2%), and 1 (4.8%), respectively; P=0.87] or the survival rate at 10 years [100%, 93.9%, and 100%, respectively; P=0.25]. The right heart catheter study revealed no pressure gradient across the orifices of both cavae in any patient. Additionally, the cardiac index immediately post-HTx was significantly low in the undersized group (P=0.008), but was similar to the other groups at 6 months post-HTx (P=0.16).

Conclusions:The mBCAT prevented caval anastomosis-related complications in size-mismatched HTx and achieved excellent hemodynamics regardless of donor size.

Background:The impact of cold ambient temperature on out-of-hospital cardiac arrest (OHCA) in aged individuals caused by cardiovascular events in indoor environments has not been investigated sufficiently.

Methods and Results:We conducted a case-crossover study. The relationship between OHCA caused by cardiovascular events and exposure to minimum temperature <0℃ was analyzed. Conditional logistic regression analysis was performed to estimate the odds ratios for the relationship between exposure to minimum temperature <0℃ and the risk of OHCA. Between January 1, 2011, and December 31, 2015, a total of 1,452 cases of OHCA were documented, and patients were screened for enrollment. A total of 458 individuals were enrolled in this analysis, and were divided into 2 groups of 110 (elderly group: 65–74 years old) and 348 (aged group: ≥75 years old). The aged individuals had a significant increased risk of OHCA after exposure to minimum temperature <0℃ (odds ratio [OR]: 1.528, 95% confidence interval [CI] 1.009–2.315, P=0.045). Cold ambient temperature was an especially significant increased risk for OHCA occurrence for males (OR: 1.997, 95% CI 1.036–3.773, P=0.039) and during winter (OR: 2.391, 95% CI 1.312–4.360, P=0.004) in the aged group.

Conclusions:Cold ambient temperature significantly affected aged individuals (≥75 years old) experiencing an OHCA caused by cardiovascular events in indoor environments.

Background:Cardiopulmonary exercise testing (CPX) is used in the prognostic evaluation of patients with heart failure with reduced ejection fraction (HFrEF). In these patients, the ventilation feedback system is dysfunctional, and overactive peripheral chemoreceptors may be responsible for the early appearance of the respiratory compensation point (RCP) after the anaerobic threshold (AT). The mechanism of RCP appearance remains unknown and very few studies have reported the relationship between RCP and heart failure. We hypothesized that the duration between the RCP and AT (RCP-AT time) can predict the severity of cardiac disorders and prognosis in patients with HFrEF.

Methods and Results:We enrolled 143 patients with HFrEF who underwent symptom-limited maximal CPX between 2012 and 2016. During a median follow-up of 1.4 years, cardiovascular death occurred in 45 participants (31%). The patients who died had a significantly shorter RCP-AT time and lower hemoglobin (Hb) levels than those who survived (P<0.001 and P=0.01, respectively). Cox regression analyses revealed RCP-AT time and Hb level to be independent predictors of cardiovascular death in patients with HFrEF (P<0.001 and P=0.018, respectively).

Conclusions:RCP-AT time can better predict prognosis in patients with HFrEF than the magnitude of increase in oxygen consumption within the isocapnic buffering domain (∆V̇O₂AT-RCP). It may be useful as a new prognostic indicator in these patients.

Background:Whether angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) exert beneficial effects in patients with concomitant heart failure (HF) and chronic kidney disease (CKD) remains uncertain. In this study, the effects of ACEI and ARB on long-term clinical outcomes in such patients were investigated.

Methods and Results:Study data were obtained from a multicenter cohort that included patients hospitalized for HF. A total of 1,601 patients with both HF and CKD were classified according to prescription of ACEI or ARB at discharge. The mortality rate was 19.0% in the ACEI/ARB treatment group (n=943) and 33.6% in the no ACEI/ARB treatment group (n=658) during follow-up. The ACEI/ARB treatment group had a significantly higher cumulative death-free survival rate than the no ACEI/ARB treatment group. Cox regression analysis showed that using ACEI or ARB was independently associated with reduced risk of all-cause death after adjusting for confounding factors. The beneficial effects of ACEI or ARB were retained after propensity score matching.

Conclusions:Prescription of an ACEI or ARB at discharge was associated with reduction in all-cause mortality in patients with acute HF and CKD. Clinicians need to be aware of the prognostic value and consider prescribing ACEI or ARB to high-risk patients.

Background:Attenuation-compensated (AC) technique was recently introduced to improve the plaque characterization of optical coherence tomography (OCT). Histological validation demonstrated promising results but the efficacy and reproducibility of this technique for assessing in-vivo tissue composition remains unclear.

Methods and Results:OCT images portraying native (n=200) and stented (n=200) segments and 31 histological cross-sections were analyzed. AC-OCT appeared superior to conventional (C)-OCT in detecting the external elastic lamina (EEM) borders (76% vs. 65.5%); AC-OCT enabled larger EEM arc detection compared with C-OCT (174.2±58.7° vs. 137.5±57.9°; P<0.001). There was poor agreement between the 2 techniques for detection of lipid in native and lipid and calcific tissue in stented segments (κ range: 0.164–0.466) but the agreement of C-OCT and AC-OCT was high for calcific tissue in native segments (κ=0.825). Intra and interobserver agreement of the 2 analysts was moderate to excellent with C-OCT (κ range: 0.681–0.979) and AC-OCT (κ range: 0.733–0.892) for all tissue types in both native and stented segments. Ex-vivoanalysis demonstrated that C-OCT was superior to AC-OCT (κ=0.545 vs. κ=0.296) for the detection of the lipid component in native segments.

Conclusions:The AC technique allows better delineation of the EEM but it remains inferior for lipid pool detection and neointima characterization. Combined AC- and C-OCT imaging may provide additional value for complete assessment of plaque and neointima characteristics.

Background:Although the effectiveness and safety of prasugrel for the prevention of cardiovascular events in patients with ischemic heart disease (IHD) undergoing percutaneous coronary intervention (PCI) have been demonstrated, long-term real-world data of Japanese unique doses are insufficient. Therefore, we report the results of an analysis of 1-year follow-up data from a postmarketing observational study (PRASFIT-Practice II).

Methods and Results:The safety and effectiveness analysis sets included 4,155 IHD patients receiving prasugrel (loading dose/maintenance dose, 20/3.75 mg) as dual antiplatelet therapy (DAPT) with aspirin. At 360 days (after treatment start), 62.2% continued DAPT. Cumulative incidences of major adverse cardiovascular events and stent thrombosis were 1.6% and 0.2%, respectively. Cumulative incidences of Thrombolysis In Myocardial Infarction (TIMI) major bleeding and TIMI major or minor bleeding were 1.0% and 2.0%, respectively. Risk factors for TIMI major or minor bleeding in the first 30 days of treatment were age ≥80 years, anemia, female sex, and liver disease, and from day 31 to the end of month 12, hypertension and peptic ulcer.

Conclusions:The 1-year follow-up results showed long-term effectiveness and safety of prasugrel at dosages approved in Japan for the treatment of IHD patients undergoing PCI.

Background:Octogenarians, who are frequently frail, represent a large proportion of patients admitted for ST-segment elevation myocardial infarction (STEMI). We investigated the relationship between frailty, assessed by the Canadian Study of Health and Aging Clinical Frailty Scale (CFS), and short- and mid-term prognoses in octogenarian STEMI patients.

Methods and Results:We used a multicenter registry data of 1,301 patients with STEMI undergoing percutaneous coronary intervention (PCI) between January 2014 and December 2016. Of them, 273 were retrospectively analyzed after categorization into 3 groups based on the preadmission CFS (CFS 1–3, 140 patients; CFS 4–5, 99 patients; and CFS 6–8, 34 patients). We evaluated the influence of CFS on overall mortality at 2 years and on non-home discharge, defined as the composite of in-hospital death and new transfer to a hospital or nursing home. During the study period (median, 565 days), the overall mortality and ratio of non-home discharge increased as CFS increased. After adjustment for multivariable analysis, the severely frail continued to be significantly associated with an increased risk of overall mortality (adjusted hazard ratio 2.37; 95% confidence interval [CI] 1.11–5.05; P=0.026) and non-home discharge (adjusted odds ratio 9.50; 95% CI 3.48–25.99; P<0.001).

Conclusions:Frailty, as assessed by CFS, had an influence on short- and mid-term prognoses in octogenarian patients with STEMI.

Background:We investigated the flow-gradient pattern characteristics and associated factors in severe bicuspid aortic stenosis (AS) compared with severe tricuspid AS.

Methods and Results:A total of 252 patients with severe AS (115 bicuspid vs. 137 tricuspid) who underwent aortic valve (AV) replacement were retrospectively analyzed. Patients were classified into 4 groups according to stroke volume index and mean pressure gradient across the AV [normal-flow–high-gradient (NF-HG), low-flow–high-gradient, normal-flow–low-gradient, low-flow–low-gradient (LF-LG)]. In 89 patients who underwent cardiac computed tomography (CT), influential structural parameters of the left ventricular outflow tract (LVOT), AV and ascending aorta were assessed. Bicuspid AS was more likely to present a NF-HG pattern (83.5% vs. 64.2%, P<0.001), and significantly fewer presented a LF-LG pattern compared with tricuspid AS. In bicuspid AS, there was a significant mismatch between geometric orifice area (GOA) on CT planimetry and effective orifice area (EOA) calculated using the echocardiographic continuity equation. Bicuspid AS presented with a larger angle between the LVOT-AV and aorta. Multivariate analysis of bicuspid AS revealed that systemic arterial compliance (β=–0.350, P=0.031) and the LVOT-AV–aorta angle (β=–0.538, P=0.001), and stroke volume index (β=0.409, P=0.008) were associated with a discrepancy between GOA and EOA.

Conclusions:Flow-gradient patterns in bicuspid AS differ from those of tricuspid AS and are associated with the structural and functional characteristics of the aorta.