The autophagic machinery is a well-conserved degradation system in eukaryotes from yeast to mammals. Autophagy has been thought of as a nonselective degradation process in which cytoplasmic proteins and organelles are degraded by fusion with lysosome. Recent studies have revealed selective forms of autophagy, such as mitochondria-specific autophagy, termed “mitophagy”. Research over the past decade has revealed that autophagy in cardiomyocytes plays a protective role, not only during hemodynamic stress but in homeostasis during aging. Hemodynamic stress and aging induce mitochondrial damage, leading to increased oxidative stress and decreased ATP production. Damaged mitochondria are generally degraded through mitophagy, which might be the main protective function of autophagy in the heart. Complete digestion of mitochondrial DNA through mitophagy is important to avoid inflammatory responses that can induce heart failure. A polyamine, spermidine, is reported to bring about an extension of lifespan and to protect the heart from age-related cardiac dysfunction, both of which are mediated through induction of autophagy. Therefore, appropriate induction of autophagy could be a novel therapeutic target for cardiovascular diseases, including heart failure. However, precise evaluation of autophagic activity in the human heart is difficult at this time, but exploitation of the novel technique of autophagy evaluation is expected for both drug discovery and clinical application.
Background: Intracellular uric acid is known to increase the protein level and channel current of atrial Kv1.5; however, mechanisms of the uric acid-induced enhancement of Kv1.5 expression remain unclear.
Methods and Results: The effects of uric acid on mRNA and protein levels of Kv1.5, as well as those of Akt, HSF1 and Hsp70, in HL-1 cardiomyocytes were studied by using qRT-PCR and Western blotting. The uptake of uric acid was measured using radio-labeled uric acid. The Kv1.5-mediated channel current was also measured by using patch clamp techniques. Uric acid up-taken by HL-1 cells significantly increased the level of Kv1.5 proteins in a concentration-dependent manner, with this increase abolished by an uric acid transporter inhibitor. Uric acid slowed degradation of Kv1.5 proteins without altering its mRNA level. Uric acid enhanced phosphorylation of Akt and HSF1, and thereby increased both transcription and translation of Hsp70; these effects were abolished by a PI3K inhibitor. Hsp70 knockdown abolished the uric acid-induced increases of Kv1.5 proteins and channel currents.
Conclusions: Intracellular uric acid could stabilize Kv1.5 proteins through phosphorylation of Akt and HSF1 leading to enhanced expression of Hsp70.
Background: Off-label dosing of direct oral anticoagulants (DOACs) is encountered clinically among patients with atrial fibrillation (AF), although data on the clinical outcomes of over- and under-dosing are lacking in Japan.
Methods and Results: We examined the clinical outcomes of off-label DOAC dosing using the SAKURA AF Registry, a prospective multicenter registry in Japan. Among 3,237 enrollees, 1,676 under any of the 4 DOAC regimens were followed up for a median of 39.3 months: 746 (45.0%), appropriate standard-dose; 477 (28.7%), appropriate low-dose; 66 (4.0%), over-dose; and 369 (22.2%) under-dose. Compared with the standard-dose group, patients in the under- and over-dose groups were significantly older and had a higher stroke risk. After multivariate adjustment, stroke/systemic embolism (SE) and death events were equivalent between the standard- and under-dose groups, but major bleeding events tended to be lower in the under-dose group (hazard ratio [HR] 0.474, P=0.0739). Composite events (stroke/SE, major bleeding, or death) were higher in the over-dose than in the standard-dose group (HR 2.714, P=0.0081).
Conclusions: Clinical outcomes were not worse for under-dose than for standard-dose users among patients with different backgrounds. Over-dose users, however, were at higher risk for all clinical events and required careful follow-up. Further studies are needed to clarify the safety and effectiveness of off-label DOAC dosing in Japan.
Background: The relationship between atrial high-rate episode (AHRE) burden (i.e., the frequency of atrial tachyarrhythmia) and heart failure (HF) risk is unclear. We hypothesized that new-onset and higher burden of AHRE are associated with HF.
Methods and Results: We included 104 consecutive patients with cardiac implantable electronic devices (CIEDs) capable of continuous atrial rhythm monitoring. Patients with AF history were excluded. To stratify patients, AHREs were evaluated only during the initial 1 year after CIED implantation. The primary endpoint was all-cause death or new-onset or worsening HF that required unplanned hospitalization or readjustment of HF drug therapy. At 1 year after CIED implantation, 34/104 patients (33%) exhibited AHREs. No difference in basal clinical characteristics except for left ventricular ejection fraction between patients with and without new-onset AHREs was found. AHRE groups had more HF events than the non-AHRE group. All patients were divided into 3 groups based on AHRE burden: none, low, and high. Worsening HF was observed in 12 patients (12%). Cox hazard analysis revealed that AHRE and higher AHRE burden were independent predictive factors for worsening HF. The high group showed a higher risk for HF than the non-AHRE groups, but no significant difference was found between the low- and non-AHRE groups.
Conclusions: New-onset higher AHRE burden was associated with subsequent risk for HF in patients with CIEDs.
Background: Data on the association between obesity and mortality in patients who require acute cardiac care are limited, so we investigated the effect of obesity on clinical outcomes in patients admitted to the cardiac intensive care unit (CICU).
Methods and Results: We reviewed 2,429 eligible patients admitted to the CICU at Samsung Medical Center between January 2012 and December 2015. After excluding 197 patients with low body mass index (BMI) to adjust for the possibility of frailty, patients were divided into 3 categories: normal BMI (n=822), 18.5–22.9 kg/m2; moderate BMI (n=1,050), 23–27.4 kg/m2; and high BMI (n=360), ≥27.5 kg/m2. The primary outcome was 28-day mortality. Overall, 124 (2.6%) of 2,232 patients died during 28-day follow-up after CICU admission. The 28-day mortality was numerically lower in the moderate (4.5%) and high (5.3%) BMI groups than in the normal BMI group (7.1%), but the difference was not statistically significant (P=0.052). After multivariable adjustment, the moderate and high BMI categories were not significant predictors of primary outcome (adjusted hazard ratio [HR] 0.74, 95% CI 0.50–1.09, P=0.127 and adjusted HR 0.80, 95% CI 0.47–1.36, P=0.404, respectively). However, Acute Physiology and Chronic Health Evaluation II scores, liver cirrhosis, malignancy, history of cardiac arrest, and need for organ support treatment were independent predictors of 28-day mortality.
Conclusions: Obesity was not associated with short-term mortality in patients requiring cardiac critical care.
Background: Bone morphogenetic proteins (BMP) 2 and 4 are implicated in the development of atherosclerosis. However, the relationships between the proteins, their main receptors and carotid intima-media thickness (cIMT), a predictive preclinical phenotype of atherosclerosis, have not been established.
Methods and Results: We screened and validated the relationships of single-nucleotide polymorphisms (SNPs) on BMP2, BMP4, BMPR1A, BMPR1B, and BMPR2 with thicker cIMT by 2 independent case-control studies that used different subject selection methods. Among 200 screened SNPs, 12 on BMPR1B were regarded as candidate genetic markers (P-value <5.0×10−4). After combining the discovery and validation studies and adjusting for traditional cardiovascular risk factors, rs4456963*G, rs4235438*T, rs2522530*T, and rs3796433*C showed significant higher odds ratios (ORs) of having thicker cIMT (adjusted ORs: 1.50–1.56; all P-values <2.5×10−4). Multivariate analyses showed that rs4456963 and rs3796433 were significantly independent determinants of cIMT thickening. The corresponding multivariate-adjusted ORs for rs4456963*G and rs3796433*C alleles were 1.50 (95% confidence interval (CI): 1.22–1.84) and 1.50 (95% CI: 1.23–1.82), respectively. Interaction between rs4456963 and rs3796433 was evident by the significantly higher OR (8.16, 95% CI: 3.12–21.3) for subjects with the GG-CC genotype. The rs4456963*G and rs3796433*C showed positively linear trends with severity of carotid atherosclerosis.
Conclusions: We identified 2 SNPs on BMPR1B showing significantly independent correlations with thicker cIMT. The study provides invaluable evidence supporting that BMPR1B is closely related to carotid atherosclerosis and a potential target for the development of therapeutic agents for atherosclerotic disease.
Background: Coffee, which contains various bioactive compounds, is one of the most popular beverages. Further accumulation of evidence is needed, however, to confirm whether coffee consumption would be effective in preventing cardiovascular disease in the general Japanese population.
Methods and Results: We evaluated the association between coffee consumption frequency (never, sometimes, 1–2 cups/day, 3–4 cups/day and ≥5 cups/day) and mortality from all causes, heart disease, and cerebrovascular disease, in 39,685 men and 43,124 women aged 40–79 years at baseline, in a 3-prefecture cohort study. The coffee consumption frequency was assessed on questionnaire. Cox proportional hazards regression modeling was used to assess the association between coffee consumption frequency and all-cause and cardiovascular disease mortality with adjustment for potential confounders. During 411,341 and 472,433 person-years in men and women, respectively, a total of 7,955 men and 5,725 women died. Coffee consumption frequency was inversely associated with all-cause mortality in both genders (P for trend<0.001). In addition, the risks of mortality from cerebrovascular disease in men (P for trend<0.001), and heart disease in women (P for trend=0.031) were inversely associated with coffee consumption.
Conclusions: In this Japanese population, coffee drinking has a preventive effect on all-cause and on cardiovascular mortality in men and/or women.
Background: The prognostic significance of the eGFR calculated by either the four-level Race Chronic Kidney Disease-Epidemiology Collaboration study equation (CKD-EPI4R) or the Chinese-modified Modification of Diet in Renal Disease equation (cMDRD) has not been compared in Asian populations with acute heart failure (AHF).
Methods and Results:A total of 3,044 patients hospitalized for AHF were enrolled. The National Death Registry was linked to identify deaths within a 5-year follow-up. Net reclassification improvement (NRI) was calculated to compare the prognostic value of either eGFR equation. During a median follow-up of 23.3 months, 1,424 (47%) patients died. Both eGFRcMDRDand eGFRCKD-EPI4Rwere independently predictive of death in the total study population (hazard ratio and 95% confidence intervals per 1-SD: 0.76, 0.71–0.81 and 0.74, 0.70–0.79, respectively), and in the subgroups of either reduced (HFrEF) or preserved (HFpEF) ejection fraction, after accounting for important confounders. With reference to eGFRcMDRD, eGFRCKD-EPI4Rmay improve the NRI by 2.0% (0.8–3.2%) for the prediction of death. The prognostic value of the CKD stages categorized by eGFRCKD-EPI4Rsignificantly outperformed eGFRcMDRDwith a categorical NRI of 9.5% (4.7–14.3%) in the total study population, 11.5% in HFrEF, and 8.3% in HFpEF.
Conclusions:Both eGFRcMDRDand eGFRCKD-EPI4Rwere independently associated with long-term survival in patients with AHF. However, the CKD stages derived from eGFRCKD-EPI4Rimproved the risk stratification of death, compared with eGFRcMDRD.
Background: Cardiac involvement occurs in more than half of the patients with light-chain amyloidosis (AL), but the characteristics, treatment and prognosis of cardiac AL (CAL) are not fully described.
Methods and Results: A total of 227 patients with CAL diagnosis between January 2009 and March 2017 at Peking Union Medical College Hospital were included. Patients with Mayo stages I, II and III AL accounted for 0.9%, 49.8% and 49.3%, respectively. Autologous stem cell transplantation, bortezomib combinations, non-bortezomib regimens and palliative treatment were given as first line therapy in 3.1%, 44.1%, 30.8% and 22.0% of patients, respectively. Overall hematological response and cardiac response were achieved in 60.6% and 37.2% of evaluable patients, respectively. The median overall survival (OS) was 17 months in all patients, and 10 months in those with Mayo stage III. In patients with Mayo stage III disease who survived for >1 month, the bortezomib group survived significantly longer than the non-bortezomib group (median OS, not reached vs. 12 months, P=0.019). Three independent prognostic factors for survival were identified: N-terminal fragment of B-type natriuretic peptide (NT-proBNP) ≥5,000 pg/mL, bone marrow plasma cells ≥10%, and systolic blood pressure <100 mmHg.
Conclusions: CAL patients had poor prognosis, but those treated with bortezomib combinations had a better outcome than the non-bortezomib group.
Background: Changes in the plasma adenosine concentration and the effects on left ventricular (LV) function and remodeling in patients with acute myocardial infarction (AMI) remain unclear.
Methods and Results: In 58 patients with AMI and 14 subjects without cardiac disease (controls), we measured the plasma adenosine concentration by LC-MS/MS. Blood samples were taken from the antecubital vein on days 0, 1, 7, and 14 after AMI, and from the controls on admission. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. There were no significant differences in the plasma adenosine concentrations among days 0 (211.5±150.2 nmol/L), 1 (192.7±141.3 nmol/L), 7 (218.8±154.1 nmol/L), and the controls (136.0±50.9 nmol/L). The plasma adenosine concentration increased significantly on day 14 (321.1±195.4 nmol/L) after AMI as compared with days 0, 1 and 7. AMI patients with a greater increase in the plasma adenosine concentration in the subacute phase showed an attenuation of LV dilation in the chronic phase. The plasma adenosine concentration in the acute phase did not affect the LV ejection fraction in the chronic phase.
Conclusions: The plasma adenosine concentration significantly increased 14 days after AMI, which may contribute to attenuation of LV dilation in the chronic phase.
Background: Landiolol, an ultra-short acting β1-selective blocker, is more effective for controlling the heart rate (HR) than digoxin in patients with atrial tachyarrhythmias and left ventricular (LV) dysfunction. The impact of the type of atrial tachyarrhythmias on the effectiveness of landiolol is uncertain. We evaluated the efficacy and safety of landiolol on tachycardiac atrial fibrillation (AF) and tachycardiac atrial flutter/atrial tachycardia (AFl/AT) in patients with reduced LV function.
Methods and Results: Seventy-seven patients treated with landiolol were retrospectively analyzed. There were no significant differences in the baseline characteristics between the AF group (n=65) and AFl/AT group (n=12). Despite a higher dosage, the %change in HR from baseline to 12 and 24 h was only −10.2±12.7% and −16.1±19.4% in the AFl/AT group, while it was −28.3±13.2% and −31.3±11.3% in the AF group (P<0.02), respectively. The prevalence of the responders to landiolol treatment was much greater in the AF group than in the AFl/AT group (P<0.001). Alternative treatments such as i.v. amiodarone and electrical cardioversion were required in 83% of the AFl/AT patients.
Conclusions: Landiolol was ineffective in the majority of AFl/AT patients. An alternative management to prevent any worsening of heart failure might be considered in those patients.
Background: The prognostic value of indices for left atrial volumes (LAV) and reservoir function measured by 3D speckle-tracking analysis (3DSTA) has not been determined.
Methods and Results: LA maximal and minimal volume indices (LAVImax, LAVImin), and LA emptying fraction (LAEmpF) were measured via 2D echocardiography (2DE) and 3DSTA in 514 patients (62% male, mean age: 66±15 years) with various cardiovascular diseases. Two cutoff values using normal±2SD (cutoff criterion 1) and receiver-operating characteristic analysis (cutoff criterion 2) were evaluated. During a mean follow-up of 720±383 days, MACE (cardiac death, nonfatal myocardial infarction, stroke and admission for heart failure) occurred in 98 patients. Kaplan-Meier survival analysis showed both cutoff criteria measured by 2DE and 3DSTA had significant predictive power for MACE (P<0.001). For cutoff criterion 1, 3DSTA measurements yielded higher hazard ratios than 2DE by Cox proportional hazard model. Cutoff criterion 2 using 3DSTA had higher average treatment effect values than 2DE by matching propensity scores on the outcome. Further, a regression model that included clinical variables, left ventricular ejection fraction and cutoff criterion 2 using 3DSTA-derived LAEmpF had significantly higher prognostic power than 2DE.
Conclusions: LA indices measured by 3DSTA had greater prognostic power for future MACE than 2DE. In particular, 3DSTA-derived LAEmpF has the potential to be a valuable prognostic tool in clinical settings.
Background: Patients who survive myocardial infarction (MI) are at risk of recurrent cardiovascular (CV) events. This study stratified post-MI patients for risk of recurrent CV events using the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P).
Methods and Results: This was an observational study that applied TRS 2°P to a consecutive cohort of post-MI patients. The primary outcome was a composite endpoint of CV death, non-fatal MI, and non-fatal ischemic stroke. A total of 1,688 post-MI patients (70.3±13.6 years; male, 63.1%) were enrolled. After a mean follow-up of 41.5±34.4 months, 405 patients (24.0%) had developed a primary outcome (9.3%/year) consisting of 278 CV deaths, 134 non-fatal MI, and 33 non-fatal strokes. TRS 2°P was strongly associated with the primary outcome. The annual incidence of primary composite endpoint for patients with TRS 2°P 0 was 1.0%, and increased progressively to 39.9% for those with TRS 2°P ≥6 (HR, 27.6; 95% CI: 9.87–77.39, P<0.001). The diagnostic sensitivity of TRS 2°P for the primary composite endpoint was 76.3% (95% CI: 72.1–80.5%). Similar associations were also observed between TRS 2°P and CV death and non-fatal MI, but not non-fatal ischemic stroke.
Conclusions: TRS 2°P reliably stratified post-MI patients for risk of future CV events.
Background: There are no reports on the effect of red blood cell distribution width (RDW) in surgical repair of tetralogy of Fallot (ToF).
Methods and Results: A total of 50 patients who underwent cardiac catheterization after surgical repair of ToF were retrospectively assessed. RDW was positively correlated with the ratio of right ventricular pressure to left ventricular pressure (RVP/LVP; P<0.0001, r2=0.57). Patients with elevated RDW had a higher RVP/LVP than those with a normal RDW (P<0.0001). Also, elevated RDW was related to elevated central venous pressure (P<0.0001), decreased mixed venous oxygen saturation (P<0.0001), greater pulmonary stenosis (P=0.003) and severe pulmonary regurgitation on echocardiography (P<0.0001), a higher rate of residual ventricular septal defect leak (P=0.004) and higher reoperation rate (P=0.009). Of the 7 patients who underwent reoperation, 6 had decrease in RDW after reoperation (P=0.012). On multivariable regression analysis, RDW was the strongest indicator of higher RVP/LVP.
Conclusions: For the first time, RDW has been shown to be a strong indicator for assessing the hemodynamics and risk of later reoperation after surgical repair of ToF.
Background: The aim of this study was to determine preferences regarding transfer of patients with congenital heart disease (CHD) attending a children’s hospital in Japan and related factors.
Methods and Results: We conducted a self-administered questionnaire survey with CHD patients >15 years of age treated at the pediatric cardiology outpatient clinic of a children’s hospital. Logistic regression analysis was used to identify factors related to patient preferences regarding the transfer. One hundred and eleven of the 122 patients given a questionnaire provided valid responses (valid response rate, 91.0%). Sixty-six subjects (64.9%) reported “not being told anything specific” by their physicians about the transfer from the children’s hospital, and 72 (59.5%) stated that they “wished to continue attending the children’s hospital”. Visiting outpatient clinic with parents (OR, 11.00; 95% CI: 2.01–60.97), having low uncertainty about continuing to attend the children’s hospital (OR, 0.95; 95% CI: 0.92–0.98), and having high uncertainty about leaving the current physician (OR, 1.04; 95% CI: 1.01–1.07) were significantly related to the patient’s wish to continue to attend the children’s hospital.
Conclusions: There is a need to improve patient education regarding the opportunities for transfer, and to develop a systematic transition program for children’s hospitals and aligned specialized adult CHD centers.
Background: Recent progress in surgical and intensive care has improved the prognosis of congenital heart disease (CHD) associated with heterotaxy syndrome. Less is known, however, about pulmonary vascular complications in these patients.
Methods and Results: We reviewed medical records of 236 patients who were diagnosed with polysplenia syndrome at 2 institutions for pediatric cardiology in Japan from 1978 to 2015. We selected and compared the clinical records of 16 patients with polysplenia who had incomplete atrioventricular septal defect (AVSD) as the polysplenia group, and 22 age-matched patients with incomplete AVSD without any syndromes including polysplenia as the control group. Although the severity of systemic to pulmonary shunt was not significantly different between the groups, mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance index (PVRI) were significantly higher in the polysplenia group than the control (mPAP, 37.3 vs. 19.1 mmHg, P=0.001; PVRI, 5.7 vs. 1.4 WU∙m2, P=0.014) before surgical intervention. On regression analysis, polysplenia influenced the development of pulmonary hypertension (PH) regardless of age at evaluation or degree of systemic to pulmonary shunt in the patients with incomplete AVSD.
Conclusions: Polysplenia syndrome is an independent risk factor for CHD-associated PH. Earlier intervention may be required to adjust the pulmonary blood flow in polysplenia syndrome with CHD to avoid the progression of PH.