Tatsuo Aoki

Coronary Endothelial Dysfunction Is Associated With Inflammation and Vasa Vasorum Proliferation in Patients With Early Atherosclerosis

Objective—Endothelial dysfunction is an early manifestation of atherosclerosis. Inflammation and vasa vasorum play a pivotal role in the pathophysiology of plaque initiation, development, and complications. Optical coherence tomography allows high-resolution imaging of tissue microstructure. Therefore, the aim of this study was to test the hypothesis that segments with endothelial dysfunction show macrophages and vasa vasorum in patients with early coronary artery disease. Approach and Results—Optical coherence tomography images were obtained from 40 patients with mild coronary atherosclerosis who underwent coronary endothelial function assessment. Optical coherence tomography findings, including macrophages and microchannels, were evaluated in 76 coronary segments corresponding to those in endothelial response to acetylcholine. Coronary artery diameter change in response to acetylcholine was more severe in segments showing macrophages (−17.7±14.7% versus −6.3±13.9%; P<0.01) and microchannels (−15.9±15.9% versus −6.4±13.5%; P<0.01) than those without. There were increasing trends of the prevalence of macrophages and microchannels with endothelial dysfunction as stratified by quartiles of coronary artery diameter change (P<0.01 and P=0.02 for trend, respectively). In particular, segments with both macrophages and microchannels (n=12) tended to have worse endothelial function than those with macrophages alone (n=15) and microchannels alone (n=15; −22.1±14.6% versus −10.9±15.6% and −10.9±15.6%; P=0.07 and P=0.06, respectively). Conclusions—Epicardial endothelial dysfunction was associated with optical coherence tomography –identified macrophages and microchannels in mild coronary atherosclerosis. The current study further supports the role of inflammation and vasa vasorum proliferation in the early stage of coronary atherosclerosis.

Evaluation of coronary adventitial vasa vasorum using 3D optical coherence tomography – Animal and human studies

Objectives This study sought to evaluate adventitial vasa vasorum (VV) in vivo with novel imaging technique of optical coherence tomography (OCT). Methods To verify OCT methods for quantification of VV, we first studied 2 swine carotid arteries in a model of focal angiogenesis by autologous blood injection, and compared microchannel volume (MCV) by OCT and VV by m-CT, and counts of those. In OCT images, adventitial MC was identified as signal-voiding areas which were located within 1 mm from the lumen-intima border. After manually tracing microchannel areas and the boundaries of lumen-intima and media-adventitial in all slices, we reconstructed 3D images. Moreover, we performed with OCT imaging in 8 recipients referred for evaluation of cardiac allograft vasculopathy at 1 year after heart transplantation. MCV and plaque volume (PV) were assessed with 3D images in each 10-mm-segment. Results In the animal study, among the 16 corresponding 1-mm-segments, there were significant correlations of count and volume between both the modalities (count r2=0.80, P<0.01; volume r2 =0.50, P<0.01) and a good agreement with a systemic bias toward underestimation with m-CT. In the human study, there was a significant positive correlation between MCV and PV (segment number=24, r2 =0.63, P<0.01). Conclusion Our results suggest that evaluation of MCV with 3D OCT imaging might be a novel method to estimate the amount of adventitial VV in vivo, and further has the potential to provide a pathophysiological insight into a role of the VV in allograft vasculopathy.

Predictive value of endothelial function by noninvasive peripheral arterial tonometry for coronary artery disease.

BackgroundEndothelial dysfunction is a key step in the initiation and progression of atherosclerosis and subsequent cardiovascular complications. We examined whether peripheral endothelial function, as assessed by fingertip reactive hyperemia-peripheral arterial tonometry (RH-PAT), can provide additional clinical value to traditional risk factors for cardiovascular diseases in predicting coronary artery disease (CAD). MethodsWe included 118 stable patients who were referred for coronary angiography for chest pain evaluation or due to abnormal stress test results. A natural logarithmic value of the RH-PAT index (Ln_RHI) was obtained before cardiac catheterization by an independent operator. Significant CAD was defined as luminal stenosis of at least 70% (≥50% at left main) and/or fractional flow reserve of up to 0.80 in one or more major coronary arteries or their major branches. ResultsLevels of Ln_RHI were significantly lower in patients with CAD (n=60) compared with patients without CAD (n=58; 0.69±0.29 vs. 0.88±0.27, P<0.001). Ln_RHI was significantly associated with CAD independent from traditional risk factors (odds ratio for a 0.1 decrease in Ln_RHI=1.25, 95% confidence interval: 1.04–1.52, P=0.01). The net reclassification index was improved when Ln_RHI was added to traditional risk factors (0.62, 95% confidence interval: 0.27–0.97, P=0.001). ConclusionPeripheral endothelial function, as assessed by RH-PAT, improved risk stratification when added to traditional risk factors. RH-PAT is potentially useful for identifying patients at high risk for CAD.

Single nucleotide polymorphisms associated with abnormal coronary microvascular function.

BackgroundSingle nucleotide polymorphisms (SNPs) are the most common source of genetic variation. Although microvascular pathology is associated with cardiovascular events, genetic phenotypes causing microvascular disease remain largely unknown. This study identifies sex-specific SNPs associated with coronary microvascular dysfunction. Methods and resultsSix hundred and forty-three patients without significant obstructive coronary heart disease were enrolled, referred for cardiac catheterization, and underwent invasive coronary microcirculatory assessment. Patient data were collected from 1529 autosomal SNPs and seven X chromosome SNPs, which were selected to represent the variability from 76 candidate genes with published associations with coronary vasoreactivity, angiogenesis, inflammation, vascular calcification, atherosclerosis risk factors, female hormones, blood coagulation, or coronary heart disease. Coronary flow reserve (CFR) was assessed by an intracoronary injection of adenosine. Patients were categorized according to a CFR above or below 2.5 and were stratified by sex.After adjusting for age, sex, and BMI, this study shows that SNPs within VEGFA and CDKN2B-AS1 are associated with abnormal CFR (P<0.005). SNPs within MYH15, VEGFA, and NT5E are associated with abnormal CFR in men. No SNPs were associated with abnormal CFR in women. ConclusionGenetic variations within defined regions of VEGFA and CDKN2B-AS1 genes are associated with coronary microvascular dysfunction. Furthermore, sex-specific allelic variants within MYH15, VEGFA, and NT5E are associated with an increased risk of coronary microvascular dysfunction in men.

Clinical Implications of Intracoronary Imaging in Cardiac Allograft Vasculopathy

Despite improvements in survival and outcomes, cardiac allograft vasculopathy (CAV), a unique form of coronary artery disease, continues to remains the leading cause of late morbidity and mortality in heart transplantation (HTx) recipients and accounts for ≈30% of all-cause mortality in this group.1 CAV can develop at any stage after HTx with an incidence of ≈7% within the first year of transplantation and 30% within 5 years.2 CAV is clinically silent and asymptomatic in its initial stages, making early diagnosis particularly challenging. Annual coronary angiography is currently the imaging modality of choice for screening and surveillance of graft coronary arteries for signs of CAV.3 However, low sensitivity of coronary angiography for detecting early-stage CAV necessitates the use of more advanced intracoronary imaging to diagnose the disease in its initial stages. Recent advances in invasive coronary imaging such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT) have shown promising results in detecting subangiographic CAV, predicting prognosis and guiding therapy.4–6 The current article reviews the present state and future directions for the use of intracoronary imaging in the diagnosis, prognosis, and treatment of CAV. Several invasive and noninvasive imaging tools have been used to screen and diagnose CAV. Some of the noninvasive tests such as dobutamine stress echocardiography, myocardial perfusion imaging (exercise and pharmacological), cardiac MRI, and coronary computed tomography angiography have been studied extensively for this purpose.7–9 Although these noninvasive tests are highly specific for angiographic CAV, they lack sensitivity in detecting subangiographic CAV.7 The diffuse nature of CAV may result in inability to identify differences in radionuclide uptake in myocardial scintigraphy testing. A 2014 meta-analysis by Wever-Pinzon et al9 demonstrated that compared with coronary angiography, coronary computed tomography angiography was 97% sensitive for detecting any CAV. However, when …

Clinical usefulness of nonhyperemic baseline Pd/Pa as a hybrid baseline Pd/Pa-fractional flow reserve strategy.

ObjectiveThe ratio of basal distal intracoronary pressure (Pd) and aortic pressure (Pa) is a nonhyperemic index for the severity of coronary artery stenosis. The aim of the current study was to evaluate the clinical usefulness of a hybrid baseline Pd/Pa–fractional flow reserve (FFR) strategy in reducing the need for hyperemia. MethodsIn this study, 570 lesions from 527 consecutive patients who had both baseline Pd/Pa and FFR determined were evaluated retrospectively. To evaluate the hybrid baseline Pd/Pa–FFR approach, patients were categorized into treatment, deferral, and undetermined groups on the basis of their baseline Pd/Pa. Thereafter, patients in the undetermined group were assigned to FFR-guided treatment or deferral on the basis of an FFR cutoff value of 0.80 or lower. Major adverse cardiac events were evaluated in a median of 48.8 months (interquartile range, 35.0–66.4). ResultsA hybrid strategy using a deferral baseline Pd/Pa value of 1.00 (negative predictive value of 100%) and a treatment baseline Pd/Pa value of 0.86 or lower (positive predictive value of 100%), and limiting adenosine to a baseline Pd/Pa value between 0.87 and 0.99 would prevent the need for vasodilator drugs in 14.6% of lesions (14.0% patients), maintaining 100% agreement with an FFR-only strategy. However, adenosine-free lesions are increased to 59.6%, with 91% agreement. There was no difference in the major adverse cardiac event-free survival rate at 5 years between baseline Pd/Pa-guided and FFR-guided treatment patients (70.8 vs. 76.3%, P=0.63), or between baseline Pd/Pa-guided and FFR-guided deferral patients (71.3 vs. 82.4%, P=0.99). ConclusionThe current study reports a range of baseline Pd/Pa values that can predict myocardial ischemia without the need for inducing hyperemia. Adoption of this hybrid baseline Pd/Pa–FFR approach can reduce the need for drug-induced hyperemia.

Attenuation in Peripheral Endothelial Function After Continuous Flow Left Ventricular Assist Device Therapy Is Associated With Cardiovascular Adverse Events

BACKGROUND Patients with heart failure (HF) have abnormal endothelial function. Although use of a continuous flow left ventricular assist device (CF-LVAD) results in significant hemodynamic improvement, the effects on systemic endothelial function are unclear. METHODS AND RESULTS Eighteen HF patients with CF-LVAD implantation were included in this prospective observational study. We measured reactive hyperemia index (RHI) before and after CF-LVAD implantation to evaluate sequential changes in endothelial function. Patients were followed clinically for the occurrence of adverse cardiovascular events, a composite of death, thrombosis, bleeding, HF, renal failure, and arrhythmia. Preoperative RHI was 1.77±0.39. Early in the postoperative period (7-14 days after operation) RHI significantly decreased to 1.19±0.31 (P<0.001, compared with preoperative RHI). At first and second follow-up (4-6 weeks and 3-7 months after operation) RHI remained lower at 1.48±0.50 (P=0.030) and 1.26±0.37 (P=0.002), respectively, compared with preoperative RHI. The decrease in early postoperative RHI relative to preoperative RHI was significantly associated with adverse cardiovascular events after CF-LVAD (age-adjusted risk ratio for 0.25 decrease in RHI, 1.35; 95% confidence interval: 1.13-1.62, P=0.001). CONCLUSIONS Peripheral endothelial function had a significant and persistent decline up to 5 months following implantation of CF-LVAD, and this decline was associated with adverse cardiovascular events. These findings may provide insight into some of the vascular complications following CF-LVAD in HF patients.

Role of endothelin in microvascular dysfunction following percutaneous coronary intervention for non-ST elevation acute coronary syndromes: a single-centre randomised controlled trial.

Objectives Percutaneous coronary intervention (PCI) for acute coronary syndromes frequently fails to restore myocardial perfusion despite establishing epicardial vessel patency. Endothelin-1 (ET-1) is a potent vasoconstrictor, and its expression is increased in atherosclerosis and after PCI. In this study, we aim to define the role of endothelin in regulating coronary microvascular blood flow and myocardial perfusion following PCI in patients with non-ST elevation acute coronary syndromes (NSTACS), by assessing whether adjunctive therapy with a selective endothelin A (ETA) receptor antagonist acutely improves postprocedural coronary microvascular blood flow. Methods In a randomised, double-blinded, placebo-controlled trial, 23 NSTACS patients were enrolled to receive an intracoronary infusion of placebo (n=11) or BQ-123 (n=12) immediately before PCI. Post-PCI coronary microvascular blood flow and myocardial perfusion were assessed by measuring Doppler-derived average peak velocity (APV), and cardiac biomarker levels were quantified. Results Compared with the placebo group, APV was significantly higher in the drug group immediately after PCI (30 (20, 37) vs 19 (9, 26) cm/s; p=0.03). Hyperaemic APV, measured post-adenosine administration, was higher in the BQ-123 group, but the difference did not achieve statistical significance (56 (48, 72) vs 46 (34, 64) cm/s; p=0.090). Maximum coronary flow reserve postprocedure was not different between the two groups (2.1 (1.6, 2.3) vs 2.5 (1.8, 3.0)). Per cent change in creatine kinase isoenzyme MB from the time of PCI to 8 and 16 hours post-PCI was significantly lower in the drug group compared with the placebo group (−17 (−26, −10) vs 26 (−15, 134); p=0.02 and −17 (−38, 14) vs 107 (2, 446); p=0.007, respectively). Conclusions Endothelin is a mediator of microvascular dysfunction during PCI in NSTACS, and adjunctive selective ETA antagonist may augment myocardial perfusion during PCI. Trial registration number NCT00586820; Results.

Utility of both Carotid Intima-media Thickness and Endothelial Function for Cardiovascular Risk Stratification in Patients with Angina-like Symptoms

BACKGROUND Myocardial perfusion scintigraphy (MPS) is used widely to assess cardiovascular risk in patients with chest pain. The utility of carotid intima-media thickness (CIMT) and endothelial function as assessed by reactive hyperemia-peripheral arterial tonometry index (RHI) in risk stratifying patients with angina-like symptoms needs to be defined. We investigated whether the addition of CIMT and RHI to Framingham Cardiovascular Risk Score (FCVRS) and MPS improves comprehensive cardiovascular risk prediction in patients presenting with angina-like symptoms. METHODS We enrolled 343 consecutive patients with angina-like symptoms suspected of having stable angina. MPS, CIMT, and RHI were performed and patients were followed for cardiovascular events for a median of 5.3 years (range 4.4-6.2). Patients were stratified by FCVRS and MPS. RESULTS During the follow-up, 57 patients (16.6%) had cardiovascular events. Among patients without perfusion defect, low RHI was significantly associated with cardiovascular events in the intermediate and high FCVRS groups (hazard ratio (HR) [95% confidence interval (CI)] of RHI ≤ 2.11 was 6.99 [1.34-128] in the intermediate FCVRS group and 6.08 [1.08-114] in the high FCVRS group). Furthermore, although MPS did not predict, only RHI predicted hard cardiovascular events (cardiovascular death, myocardial infarction, and stroke) independent from FCVRS, and adding RHI to FCVRS improved net reclassification index (20.9%, 95% CI 0.8-41.1, p = 0.04). Especially, RHI was significantly associated with hard cardiovascular events in the high FCVRS group (HR [95% CI] of RHI ≤ 1.93 was 5.66 [1.54-36.4], p = 0.007). CONCLUSIONS Peripheral endothelial function may improve discrimination in identifying at-risk patients for future cardiovascular events when added to FCVRS-MPS-based risk stratification.

PREDICTIVE VALUE OF ENDOTHELIAL FUNCTION BY NON-INVASIVE PERIPHERAL ARTERIAL TONOMETRY FOR CORONARY ARTERY DISEASE

Endothelial dysfunction is an early stage of atherosclerosis and is associated with cardiovascular events. We examined whether peripheral endothelial function, as assessed by fingertip reactive hyperemia-peripheral arterial tonometry (RH-PAT) can provide an additional clinical value to Framingham