Early therapeutic effects of adaptive servo-ventilation on cardiac sympathetic nervous function in patients with heart failure evaluated using a combination of 11C-HED PET and 123I-MIBG SPECT.

RATIONALE: Adaptive servo-ventilation (ASV), a novel respiratory support therapy for sleep disorders, may improve cardiac function in heart failure (HF). However, the reasons that ASV improves cardiac function have not been fully studied especially in sympathetic nervous function (SNF). The purpose of the present study was to investigate the effects of ASV therapy on cardiac SNF in patients with HF. METHODS: We evaluated ASV therapeutic effects before and 6 months after ASV therapy in 9 HF patients [57.3 ± 17.3 years old, left ventricular ejection fraction (LVEF) 36.1 ± 16.7%]. We performed echocardiography, polysomnography, biomarkers, 11C-hydroxyephedrine (HED) PET as a presynaptic function marker and planar 123I-metaiodobenzylguanidine (MIBG) to evaluate washout rate. RESULTS: ASV therapy reduced apnea-hypopnea index (AHI) and improved plasma brain natriuretic peptide (BNP) concentration. In 123I-MIBG imaging, the early heart/mediastinum (H/M) ratio increased after ASV therapy (2.19 ± 0.58 to 2.40 ± 0.67; P = 0.045). Washout rate did not change (23.8 ± 7.3% to 23.8 ± 8.8%; P = 0.122). Global 11C-HED retention index (RI) improved from 0.068 ± 0.033/s to 0.075 ± 0.034/s (P = 0.029). CONCLUSIONS: ASV reduced AHI and improved BNP. ASV might initially improve presynaptic cardiac sympathetic nervous function in HF patients after 6 months of treatment.

Impact of admission liver stiffness on long-term clinical outcomes in patients with acute decompensated heart failure.

Liver stiffness (LS) has been reported to be a marker of liver congestion caused by elevated central venous pressure in heart failure (HF) patients. Recent studies demonstrated that LS could be non-invasively measured by virtual touch quantification (VTQ). However, its prognostic implication in patients with acute decompensated heart failure (ADHF) is unclear. This study sought to determine whether LS measured by VTQ could be a determinant of subsequent adverse events in ADHF patients. We prospectively recruited 70 ADHF patients who underwent LS measurement by VTQ on admission in our university hospital between June 2016 and April 2018. The primary outcome of interest was the composite of all-cause mortality and worsening HF. During a median follow-up period of 272 (interquartile range 122-578) days, there were 26 (37%) events, including 5 (7%) deaths and 21 (30%) cases of worsening HF. The c-index of LS for predicting the composite of adverse events was 0.77 (95% CI 0.66-0.88), and the optimal cut-off value of LS was 1.50 m/s. Adverse events were more frequently observed in patients with high LS (≥ 1.50 m/s) compared to those with low LS (< 1.50 m/s). Multivariable Cox regression analyzes revealed that higher LS was independently associated with increased subsequent risk of adverse events after adjustment for confounders. In conclusion, high admission LS was an independent determinant of worse clinical outcomes in patients with ADHF. This finding suggests that LS on admission is useful for risk stratification of patients with ADHF.

Value of Virtual Touch Quantification Elastography for Assessing Liver Congestion in Patients With Heart Failure.

BACKGROUND: Heart failure (HF) causes organ congestion, which is thought to increase organ stiffness. The virtual touch quantification (VTQ) method can be used to assess liver stiffness in patients with chronic liver diseases. This study aimed to measure liver and kidney stiffness using VTQ and to determine its value for assessing organ congestion in patients with HF. METHODS AND RESULTS: This study included 10 normal subjects and 38 HF patients (age 52.3±16.7 years, left ventricular ejection fraction 27.0±9.4%, plasma B-type natriuretic peptide [BNP] 1,297.3±1,155.1 pg/ml). We investigated the relationships between clinical characteristics and hemodynamics and liver and kidney stiffness, and assessed the effects of medical treatment on these measurements. Liver stiffness was significantly higher in HF patients (1.17±0.13 m/s vs. 2.03±0.91 m/s, P=0.004) compared with normal subjects, but kidney stiffness was similar in both groups. Central venous pressure (CVP) (P=0.021) and BNP (P=0.025) were independent predictive factors for increased liver stiffness in HF patients. Liver stiffness decreased significantly from 2.37±1.09 to 1.27±0.33 m/s (P<0.001) after treatment. Changes in liver stiffness in HF patients significantly correlated with changes in CVP (R=0.636, P=0.014) and cardiac index (R=-0.557, P=0.039) according to univariate analysis, and with changes in CVP in multivariate analysis. CONCLUSIONS: Liver stiffness measured by noninvasive VTQ methods can be used to assess liver congestion and therapeutic effects in patients with HF. (Circ J 2016; 80: 1187-1195).

Higher Hemoglobin A1c After Discharge Is an Independent Predictor of Adverse Outcomes in Patients With Acute Coronary Syndrome　- Findings From the PACIFIC Registry.

BACKGROUND: Optimal medical therapy (OMT) and the management of coronary risk factors are necessary for secondary prevention of major adverse cardiac and cerebrovascular events (MACCE) in post-acute coronary syndrome (ACS) patients. However, the effect of post-discharge patient adherence has not been investigated in Japanese patients. METHODS AND RESULTS: The Prevention of AtherothrombotiC Incidents Following Ischemic Coronary Attack (PACIFIC) registry was a multicenter, prospective observational study of 3,597 patients with ACS. Death or MACCE occurred in 229 patients between hospitalization and up to 1 year after discharge. Among 2,587 patients, the association between OMT adherence and risk factor control at 1 year and MACCE occurring between 1 and 2 years after discharge was assessed. OMT was defined as the use of antiplatelet agents, angiotensin-converting enzyme inhibitors, ß-blockers, and statins. Risk factor targets were: low-density lipoprotein-cholesterol <100 mg/dl, HbA1c <7.0%, non-smoking status, blood pressure <130/80 mmHg, and 18.5≤body mass index≤24.9 kg/m(2). The incidence of MACCE was 1.8% and associated with female sex (P=0.020), age ≥75 years (P=0.004), HbA1c ≥7.0% (P=0.004), LV ejection fraction <35% (P<0.001), estimated glomerular filtration rate <60 ml/min (P=0.008), and history of cerebral infarction (P=0.003). In multivariate analysis, lower post-discharge HbA1c was strongly associated with a lower risk of MACCE after ACS (P=0.004). CONCLUSIONS: Hyperglycemia after discharge is a crucial target for the prevention of MACCE in post-ACS patients. (Circ J 2016; 80: 1607-1614).

Adaptive Servo-Ventilation Has More Favorable Acute Effects on Hemodynamics Than Continuous Positive Airway Pressure in Patients With Heart Failure.

Adaptive servo-ventilation (ASV) has been attracting attention as a novel respiratory support therapy for heart failure (HF). However, the acute hemodynamic effects have not been compared between ASV and continuous positive airway pressure (CPAP) in HF patients.We studied 12 consecutive patients with stable chronic HF. Hemodynamic measurement was performed by right heart catheterization before and after CPAP 5 cmH2O, CPAP 10 cmH2O, and ASV for 15 minutes each.Heart rate, blood pressure, pulmonary capillary wedge pressure (PCWP), and stroke volume index (SVI) were not changed by any intervention. Right atrial pressure significantly increased after CPAP 10 cmH2O (3.6 ± 3.3 to 6.7 ± 1.6 mmHg, P = 0.005) and ASV (4.1 ± 2.6 to 6.8 ± 1.5 mmHg, P = 0.026). Cardiac index was significantly decreased by CPAP 10 cmH2O (2.3 ± 0.4 to 1.9 ± 0.3 L/minute/m(2), P = 0.048), but was not changed by ASV (2.3 ± 0.4 to 2.0 ± 0.3 L/ minute/m(2), P = 0.299). There was a significant positive correlation between baseline PCWP and % of baseline SVI by CPAP 10 cmH2O (r = 0.705, P < 0.001) and ASV (r = 0.750, P < 0.001). ASV and CPAP 10 cmH2O had significantly greater slopes of this correlation than CPAP 5 cmH2O, suggesting that patients with higher PCWP had a greater increase in SVI by ASV and CPAP 10 cmH2O. The relationship between baseline PCWP and % of baseline SVI by ASV was shifted upwards compared to CPAP 10 cmH2O. Furthermore, based on the results of a questionnaire, patients accepted CPAP 5 cmH2O and ASV more favorably compared to CPAP 10 cmH2O.ASV had more beneficial effects on acute hemodynamics and acceptance than CPAP in HF patients.

Cardiac magnetic resonance performs better in the detection of functionally significant coronary artery stenosis compared to single-photon emission computed tomography and dobutamine stress echocardiography.

BACKGROUND: Fractional flow reserve (FFR) measured on catheterization is now widely used for the diagnosis of functional myocardial ischemia in patients with coronary artery disease (CAD). FFR, however, is invasive and carries potential procedural complications. Therefore, the aim of this study was to compare the diagnostic capability in functionally significant stenosis identified on FFR, between cardiac magnetic resonance myocardial perfusion imaging (CMR-MPI), single-photon emission computed tomography MPI (SPECT-MPI), and dobutamine stress echocardiography (DSE) in patients with CAD. METHODS AND RESULTS: A total of 25 patients who had at least 1 angiographic stenosis ≥50% on coronary angiography was studied. CMR-MPI, SPECT-MPI and DSE were done before FFR measurement. FFR was measured in all 3 major epicardial coronary arteries. Out of 71 vascular territories excluding 4 territories due to inadequate imaging, 29 (41%) had FFR <0.80. The sensitivity of CMR-MPI was significantly higher than that of SPECT-MPI and DSE (P=0.02 and P=0.001, respectively). The area under the receiver operating characteristic curve (AUC) for CMR-MPI (AUC, 0.92) was significantly greater than for SPECT-MPI (AUC, 0.73; P=0.006) and DSE (AUC, 0.69; P<0.001). CONCLUSIONS: CMR-MPI performed well in the detection of functionally significant stenosis defined according to FFR, and had the highest diagnostic sensitivity among the 3 modalities tested in patients with CAD.

Acute hemodynamic effects of adaptive servo-ventilation in patients with heart failure.

BACKGROUND: Adaptive servo-ventilation (ASV) improves cardiac function in patients with heart failure (HF). We compared the hemodynamics of control and HF patients, and identified the predictors for acute effects of ASV in HF. METHODS AND RESULTS: We performed baseline echocardiographic measurements and hemodynamic measurements at baseline and after 15 min of ASV during cardiac catheterization in 11 control and 34 HF patients. Heart rate and blood pressure did not change after ASV in either the control or HF group. Stroke volume index (SVI) decreased from 49.3±7.6 to 41.3±7.6 ml/m2 in controls (P<0.0001) but did not change in the HF patients (from 34.8±11.5 to 32.8±8.9 ml/m2, P=0.148). In the univariate analysis, pulmonary capillary wedge pressure (PCWP), mitral regurgitation (MR)/left atrial (LA) area, E/A, E/e', and the sphericity index defined by the ratio between the short-axis and long-axis dimensions of the left ventricle significantly correlated with % change of SVI from baseline during ASV. PCWP and MR/LA area were independent predictors by multivariate analysis. Moreover, responders (15 of 34 HF patients; 44%) categorized by an increase in SVI showed significantly higher PCWP, MR, and sphericity index. CONCLUSIONS: Left ventricular structure and MR, as well as PCWP, could predict acute favorable effects on hemodynamics by ASV therapy in HF patients.

Intravascular ultrasound findings of the protrusion of the EXOSEAL plug that caused acute limb ischemia.

Vascular closure devices have become popular for rapid hemostasis and early ambulation. However, there are a few reports of complications. We presented a case with acute limb ischemia caused by the protrusion of the EXOSEAL plug into the vessel. Intravascular ultrasound imaging helped determine the plug that caused the occlusion.

Effects of coronary revascularization on global coronary flow reserve in stable coronary artery disease.

Aims: Coronary flow reserve (CFR) is an integrated measure of the entire coronary vasculature, and is a powerful prognostic marker in coronary artery disease (CAD). The extent to which coronary revascularization can improve CFR is unclear. This study aimed to evaluate the impact of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) on CFR in patients with stable CAD. Methods and results: In a prospective, multicentre observational study, CFR was measured by 15O-water positron emission tomography as the ratio of stress to rest myocardial blood flow at baseline and 6 months after optimal medical therapy (OMT) alone, PCI, or CABG. Changes in the SYNTAX and Leaman scores were angiographically evaluated as indicators of completeness of revascularization. Follow-up was completed by 75 (25 OMT alone, 28 PCI, and 22 CABG) out of 82 patients. The median SYNTAX and Leaman scores, and baseline CFR were 14.5 [interquartile range (IQR): 8-24.5], 5.5 (IQR: 2.5-12.5), and 1.94 (IQR: 1.67-2.66), respectively. Baseline CFR was negatively correlated with the SYNTAX (ρ = -0.40, P < 0.001) and Leaman scores (ρ = -0.33, P = 0.004). Overall, only CABG was associated with a significant increase in CFR [1.67 (IQR: 1.14-1.96) vs. 1.98 (IQR: 1.60-2.39), P < 0.001]. Among patients with CFR <2.0 (n = 41), CFR significantly increased in the PCI [1.70 (IQR: 1.42-1.79) vs. 2.21 (IQR: 1.78-2.49), P = 0.002, P < 0.001 for interaction between time and CFR] and CABG groups [1.28 (IQR: 1.13-1.80) vs. 1.86 (IQR: 1.57-2.22), P < 0.001]. The reduction in SYNTAX or Leaman scores after PCI or CABG was independently associated with the percent increase in CFR after adjusting for baseline characteristics (P = 0.012 and P = 0.011, respectively). Conclusion: Coronary revascularization ameliorated reduced CFR in patients with obstructive CAD. The degree of improvement in angiographic CAD burden by revascularization was correlated with magnitude of improvement in CFR.

Novel echocardiographic method to assess left ventricular chamber stiffness and elevated end-diastolic pressure based on time-velocity integral measurements of pulmonary venous and transmitral flows.

Aims: The detection of increased left ventricular (LV) chamber stiffness may play an important role in assessing cardiac patients with potential but not overt heart failure. A non-invasive method to estimate it is not established. We investigated whether the echocardiographic backward/forward flow volume ratio from the left atrium (LA) during atrial contraction reflects the LV chamber stiffness. Methods and results: We studied 62 patients who underwent cardiac catheterization and measured their left ventricular end-diastolic pressure (LVEDP) and pressure increase during atrial contraction (ΔPa) from the LV pressure waveform. Using the echocardiographic biplane method of disks, we measured the LV volume change during atrial contraction indexed to the body surface area (ΔVa), and ΔPa/ΔVa was calculated as a standard for the LV operating chamber stiffness. Using pulsed Doppler echocardiography, we measured the time-velocity integral (TVI) of the backward pulmonary venous (PV) flow during atrial contraction (IPVA) and the ratio of IPVA to the PV flow TVI throughout a cardiac cycle (FPVA). We also measured the TVI of the atrial systolic forward transmitral flow (IA) and the ratio of the IA to the transmitral TVI during a cardiac cycle (FA) and calculated IPVA/IA and FPVA/FA. IPVA/IA and FPVA/FA were well correlated with ΔPa/ΔVa (r = 0.79 and r = 0.81) and LVEDP (r = 0.73 and r = 0.77). The areas under the ROC curve to discriminate LVEDP >18 mmHg were 0.90 for IPVA/IA and 0.93 for FPVA/FA. Conclusion: The FPVA/FA, the backward/forward flow volume ratio from the LA during atrial contraction, is useful for non-invasive assessments of LV chamber stiffness and elevated LVEDP.

Immunohistochemical identification of Propionibacterium acnes in granuloma and inflammatory cells of myocardial tissues obtained from cardiac sarcoidosis patients.

BACKGROUND: Although rare, cardiac sarcoidosis (CS) is potentially fatal. Early diagnosis and intervention are essential, but histopathologic diagnosis is limited. We aimed to detect Propionibacterium acnes, a commonly implicated etiologic agent of sarcoidosis, in myocardial tissues obtained from CS patients. METHODS AND RESULTS: We examined formalin-fixed paraffin-embedded myocardial tissues obtained by surgery or autopsy and endomyocardial biopsy from patients with CS (n = 26; CS-group), myocarditis (n = 15; M-group), or other cardiomyopathies (n = 39; CM-group) using immunohistochemistry (IHC) with a P. acnes-specific monoclonal antibody. We found granulomas in 16 (62%) CS-group samples. Massive (≥14 inflammatory cells) and minimal (<14 inflammatory cells) inflammatory foci, respectively, were detected in 16 (62%) and 11 (42%) of the CS-group samples, 10 (67%) and 10 (67%) of the M-group samples, and 1 (3%) and 18 (46%) of the CM-group samples. P. acnes-positive reactivity in granulomas, massive inflammatory foci, and minimal inflammatory foci were detected in 10 (63%), 10 (63%), and 8 (73%) of the CS-group samples, respectively, and in none of the M-group and CM-group samples. CONCLUSIONS: Frequent identification of P. acnes in sarcoid granulomas of originally aseptic myocardial tissues suggests that this indigenous bacterium causes granuloma in many CS patients. IHC detection of P. acnes in massive or minimal inflammatory foci of myocardial biopsy samples without granulomas may be useful for differentiating sarcoidosis from myocarditis or other cardiomyopathies.

Myocardial Immunocompetent Cells and Macrophage Phenotypes as Histopathological Surrogates for Diagnosis of Cardiac Sarcoidosis in Japanese.

BACKGROUND: The histological diagnosis of cardiac sarcoidosis (CS) is based on the presence of myocardial granulomas; however, the sensitivity of endomyocardial biopsy is relatively low. We investigated whether immunocompetent cells including dendritic cells (DC) and macrophages in nongranuloma sections of endomyocardial biopsy samples could be histopathological surrogates for CS diagnosis. METHODS AND RESULTS: The numbers of DC and macrophages were investigated in 95 consecutive CS patients and 50 patients with nonischemic cardiomyopathy as controls. All patients underwent endomyocardial biopsy, and immunohistochemical staining was performed on all samples. We examined these immunocompetent cells in nongranuloma sections in CS patients diagnosed by the presence of myocardial granulomas (n=26) and in CS patients without myocardial granulomas diagnosed by the Japanese Ministry of Health Welfare 2007 criteria (n=65) or the Heart Rhythm Society 2014 criteria (n=26). In CS patients with and without myocardial granulomas, CD209+ DC and CD68+ macrophages were more frequently observed (P<0.01) and CD163+M2 macrophages were less frequently observed (P<0.01) in nongranuloma sections compared to controls. Furthermore, the combination of decreased CD163+M2/CD68+ macrophage ratio and increased number of CD209+ DC in nongranuloma sections of CS patients demonstrated high specificity (100%, 95% CI 92.7-100) for CS diagnosis with each diagnostic criteria and the presence of myocardial granulomas. CONCLUSIONS: Increased number of DC and decreased M2 among all macrophages in nongranuloma sections of myocardium showed high specificity for CS diagnosis, suggesting DC and macrophage phenotypes as histopathological surrogates for the diagnosis of CS.

Serum choline plasmalogens-those with oleic acid in sn-2-are biomarkers for coronary artery disease.

BACKGROUND: Identifying risk factors is crucial for preventing cardiovascular events, but there are no widely accepted predictive biomarkers. In our previous study of Japanese asymptomatic cohorts, we performed global analysis of serum ether glycerophospholipids (Egp) molecular profiles, and found that choline plasmalogens (PlsCho; 1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphocholine), particularly those containing oleic acid (18:1) in the sn-2 position, were strongly associated with a wide range of risk factors for metabolic syndrome/atherosclerosis. METHODS: We determined serum concentrations of Egp molecular species of coronary artery disease patients (n=50; 31 males and 19 females) by LC/MS/MS, and plasmalogen (Pls; 1-O-alk-1'-enyl-2-acyl-sn-glycerophospholipids) contents in lipoprotein fractions by HPLC using radioactive iodine. RESULTS: We found that the serum concentrations of ether choline glycerophospholipids (EgpCho), particularly PlsCho, were not only significantly lower in males with significant coronary stenosis but also associated with atherosclerosis-related parameters, and their association was stronger than either high-density lipoprotein cholesterol or adiponectin. In addition, serum PlsCho containing 18:1 or linoleic acid (18:2) in sn-2 showed the highest correlations with a wide range of atherogenic parameters among PlsCho molecular species. CONCLUSION: These results verify our previous findings that serum PlsCho, particularly those containing 18:1 in sn-2, may serve as reliable biomarkers for atherosclerosis.