Coronary Flow Variations Following Percutaneous Coronary Intervention Affect Diastolic Nonhyperemic Pressure Ratios More Than the Whole Cycle Ratios.

Background Post-percutaneous coronary intervention (PCI) fractional flow reserve ≥0.90 is an accepted marker of procedural success, and a cutoff of ≥0.95 has recently been proposed for post-PCI instantaneous wave-free ratio. However, stability of nonhyperemic pressure ratios (NHPRs) post-PCI is not well characterized, and transient reactive submaximal hyperemia post-PCI may affect their precision. We performed this study to assess stability and reproducibility of NHPRs post-PCI. Methods and Results Fifty-seven patients (age, 63.77±10.67 years; men, 71%) underwent hemodynamic assessment immediately post-PCI and then after a recovery period of 10, 20, and 30 minutes and repeated at 3 months. Manual offline analysis was performed to derive resting and hyperemic pressure indexes (Pd/Pa resting pressure gradient, mathematically derived instantaneous wave-free ratio, resting full cycle ratio, and fractional flow reserve) and microcirculatory resistances (basal microvascular resistance and index of microvascular resistance). Transient submaximal hyperemia occurring post-PCI was demonstrated by longer thermodilution time at 30 minutes compared with immediately post-PCI; mean difference of thermodilution time was 0.17 seconds (95% CI, 0.07-0.26 seconds; P=0.04). Basal microcirculatory resistance was also higher at 30 minutes than immediately post-PCI; mean difference of basal microvascular resistance was 10.89 mm Hg.s (95% CI, 2.25-19.52 mm Hg.s; P=0.04). Despite this, group analysis confirmed no significant differences in the values of resting whole cycle pressure ratios (Pd/Pa and resting full cycle ratio) as well as diastolic pressure ratios (diastolic pressure ratio and mathematically derived instantaneous wave-free ratio). Whole cardiac cycle NHPRs demonstrated the best overall stability post-PCI, and 1 in 5 repeated diastolic NHPRs crossed the clinical decision threshold. Conclusions Whole cycle NHPRs demonstrate better reproducibility and clinical precision post-PCI than diastolic NHPRs, possibly because of less perturbation from predominantly diastolic reactive hyperemia and left ventricular stunning. Registration URL: https://clinicaltrials.gov/ct2/show/NCT03502083; Unique identifier: NCT03502083 and URL: https://clinicaltrials.gov/ct2/show/NCT03076476; Unique identifier: NCT03076476.

Adenosine-Induced Coronary Steal Is Observed in Patients Presenting With ST-Segment-Elevation Myocardial Infarction.

Background Adenosine is used to treat no-reflow in the infarct-related artery (IRA) during ST-segment-elevation myocardial infarction intervention. However, the physiological effect of adenosine in the IRA is variable. Coronary steal-a reduction of blood flow to the distal coronary bed-can occur in response to adenosine and this is facilitated by collaterals. We investigated the effects of adenosine on coronary flow reserve (CFR) in patients presenting with ST-segment-elevation myocardial infarction to better understand the physiological mechanism underpinning the variable response to adenosine. Methods and Results Pressure-wire assessment of the IRA after percutaneous coronary intervention was performed in 93 patients presenting with ST-segment-elevation myocardial infarction to calculate index of microvascular resistance, CFR, and collateral flow index by pressure. Modified collateral Rentrop grade to the IRA was recorded, as was microvascular obstruction by cardiac magnetic resonance imaging. Coronary steal (CFR <0.9), no change in flow (CFR=0.9-1.1), and hyperemic flow (CFR >1.1) after adenosine occurred in 19 (20%), 15 (16%), and 59 (63%) patients, respectively. Patients with coronary steal had higher modified Rentrop score to the IRA (1 [0, 1.75] versus 0 [0, 1], P<0.001) and a higher collateral flow index by pressure (0.25±0.10 versus 0.15±0.10, P=0.004) than the hyperemic group. The coronary steal group also had significantly higher index of microvascular resistance (61.68 [28.13, 87.04] versus 23.93 [14.67, 37.00], P=0.006) and had more disease (stenosis >50%) in the donor arteries (52.63% versus 22.03%, P=0.02) than the hyperemic group. Conclusions Adenosine-induced coronary steal may be responsible for a reduction in coronary flow reserve in a proportion of patients presenting with ST-segment-elevation myocardial infarction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03145194. URL: https://www.isrctn.com; Unique identifier: ISRCTN3176727.

GLP-1 vasodilatation in humans with coronary artery disease is not adenosine mediated.

BACKGROUND: Incretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive. We have previously shown that glucagon-like peptide (GLP)-1 is a coronary vasodilator and we sought to investigate if this is an adenosine-mediated effect. METHODS: We recruited 41 patients having percutaneous coronary intervention (PCI) for stable angina and allocated them into four groups administering a specific study-related infusion following successful PCI: GLP-1 infusion (Group G) (n = 10); Placebo, normal saline infusion (Group P) (n = 11); GLP-1 + Theophylline infusion (Group GT) (n = 10); and Theophylline infusion (Group T) (n = 10). A pressure wire assessment of coronary distal pressure and flow velocity (thermodilution transit time-Tmn) at rest and hyperaemia was performed after PCI and repeated following the study infusion to derive basal and index of microvascular resistance (BMR and IMR). RESULTS: There were no significant differences in the demographics of patients recruited to our study. Most of the patients were not diabetic. GLP-1 caused significant reduction of resting Tmn that was not attenuated by theophylline: mean delta Tmn (SD) group G - 0.23 s (0.27) versus group GT - 0.18 s (0.37), p = 0.65. Theophylline alone (group T) did not significantly alter resting flow velocity compared to group GT: delta Tmn in group T 0.04 s (0.15), p = 0.30. The resulting decrease in BMR observed in group G persisted in group GT: - 20.83 mmHg s (24.54 vs. - 21.20 mmHg s (30.41), p = 0.97. GLP-1 did not increase circulating adenosine levels in group GT more than group T: delta median adenosine - 2.0 ng/ml (- 117.1, 14.8) versus - 0.5 ng/ml (- 19.6, 9.4); p = 0.60. CONCLUSION: The vasodilatory effect of GLP-1 is not abolished by theophylline and GLP-1 does not increase adenosine levels, indicating an adenosine-independent mechanism of GLP-1 coronary vasodilatation. TRIAL REGISTRATION: The local research ethics committee approved the study (National Research Ethics Service-NRES Committee, East of England): REC reference 14/EE/0018. The study was performed according to institutional guidelines, was registered on http://www.clinicaltrials.gov (unique identifier: NCT03502083) and the study conformed to the principles outlined in the Declaration of Helsinki.

The role of Glucagon-Like Peptide 1 Loading on periprocedural myocardial infarction During elective PCI (GOLD-PCI study): A randomized, placebo-controlled trial.

BACKGROUND: The incretin hormone glucagon-like peptide 1 (GLP-1) has been shown to protect against lethal ischemia-reperfusion injury in animal models and against nonlethal ischemia reperfusion injury in humans. Furthermore, GLP-1 receptor agonists have been shown to reduce major adverse cardiovascular and cerebrovascular events (MACCE) in large-scale studies. We sought to investigate whether GLP-1 reduced percutaneous coronary intervention (PCI)-associated myocardial infarction (PMI) during elective PCI. METHODS: The study was a randomized, double-blind controlled trial in which patients undergoing elective PCI received an intravenous infusion of either GLP-1 at 1.2 pmol/kg/min or matched 0.9% saline placebo before and during the procedure. Randomization was performed in 1:1 fashion, with stratification for diabetes mellitus. Six-hour cardiac troponin I (cTnI) was measured with a primary end point of PMI defined as rise ≫×5 upper limit of normal (280 ng/L). Secondary end points included cTnI rise and MACCE at 12 months. RESULTS: A total of 192 patients were randomized with 152 (79%) male and a mean age of 68.1 ±â€¯8.9 years. No significant differences in patient demographics were noted between the groups. There was no difference in the rate of PMI between GLP-1 and placebo (9 [9.8%] vs 8 [8.3%], P = 1.0) or in the secondary end points of difference in median cTnI between groups (9.5 [0-88.5] vs 20 [0-58.5] ng/L, P = .25) and MACCE at 12 months (7 [7.3%] vs 9 [9.4%], P = .61). CONCLUSIONS: In this randomized, placebo-controlled trial, GLP-1 did not reduce the low incidence of PMI or abrogate biomarker rise during elective PCI, nor did it influence the 12-month MACCE rate which also remained low. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov Number: NCT02127996https://clinicaltrials.gov/ct2/show/NCT02127996.

Stunning and Right Ventricular Dysfunction Is Induced by Coronary Balloon Occlusion and Rapid Pacing in Humans: Insights From Right Ventricular Conductance Catheter Studies.

BACKGROUND: We sought to determine whether right ventricular stunning could be detected after supply (during coronary balloon occlusion [BO]) and supply/demand ischemia (induced by rapid pacing [RP] during transcatheter aortic valve replacement) in humans. METHODS AND RESULTS: Ten subjects with single-vessel right coronary artery disease undergoing percutaneous coronary intervention with normal ventricular function were studied in the BO group. Ten subjects undergoing transfemoral transcatheter aortic valve replacement were studied in the RP group. In both, a conductance catheter was placed into the right ventricle, and pressure volume loops were recorded at baseline and for intervals over 15 minutes after a low-pressure BO for 1 minute or a cumulative duration of RP for up to 1 minute. Ischemia-induced diastolic dysfunction was seen 1 minute after RP (end-diastolic pressure [mm Hg]: 8.1±4.2 versus 12.1±4.1, P<0.001) and BO (end-diastolic pressure [mm Hg]: 8.1±4.0 versus 8.7±4.0, P=0.03). Impairment of systolic and diastolic function after BO remained at 15-minutes recovery (ejection fraction [%]: 55.7±9.0 versus 47.8±6.3, P<0.01; end-diastolic pressure [mm Hg]: 8.1±4.0 versus 9.2±3.9, P<0.01). Persistent diastolic dysfunction was also evident in the RP group at 15-minutes recovery (end-diastolic pressure [mm Hg]: 8.1±4.1 versus 9.9±4.4, P=0.03) and there was also sustained impairment of load-independent indices of systolic function at 15 minutes after RP (end-systolic elastance and ventriculo-arterial coupling [mm Hg/mL]: 1.25±0.31 versus 0.85±0.43, P<0.01). CONCLUSIONS: RP and right coronary artery balloon occlusion both cause ischemic right ventricular dysfunction with stunning observed later during the procedure. This may have intraoperative implications in patients without right ventricular functional reserve.

Mid-term clinical outcomes of ABSORB bioresorbable vascular scaffold implantation in a real-world population: A single-center experience.

BACKGROUND: Available data on the use of the ABSORB bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, CA) in real-world patients is limited. The aim of this study was to assess the mid-term clinical outcomes in a real-world population treated with ABSORB BVS. METHODS AND MATERIALS: We retrospectively evaluated all patients treated with ABSORB at Papworth Hospital, Papworth Everard, UK between July 2012 and July 2014. A total of 108 patients (126 lesions) were identified. Clinical follow-up was performed on all subjects by clinic visit or telephone interview. RESULTS: Most patients were male (91.7%) with a relative high incidence of previous myocardial infarction (MI) (40.7%). Clinical presentation was equally divided between stable angina and acute coronary syndrome (ACS) (51.8% vs. 48.2%, p=0.59). Of the ACS patients, 26.9% presented with ST-elevation myocardial MI. Intravascular imaging was used in all cases. Predilatation (92.9%) and postdilatation (82.5%) were frequently performed. Major adverse cardiac event (MACE) rates defined as the composite of all-cause death, follow-up MI and target vessel revascularization were 2.5% at 6-month and 4.5% at 1-year. The 1-year target lesion failure rate, defined as the composite of cardiac death, target-vessel MI and target lesion revascularization was 1.9%. There was 1 case of subacute stent thrombosis. CONCLUSIONS: The use of ABSORB BVS in real-world patients appears to be associated with good mid-term clinical outcomes when guided by intravascular imaging. Larger studies are required to evaluate further the role of BVS in routine clinical practice and examine how this compares to metallic devices. SUMMARY: Available data on the use of the ABSORB BVS in real-world patients is limited. We retrospectively evaluated all patients treated with ABSORB BVS between July 2012 and July 2014. A total of 108 patients (126 lesions) were identified. Clinical presentation was equally divided between stable angina and acute coronary syndrome (51.8% vs. 48.2%, p=0.59). Predilatation (92.9%) and postdilatation (82.5%) were frequently performed. Estimated MACE rates at 6-month and 1-year were 2.5% and 4.5% respectively, with a 1-year TLF rate of 1.9%. These results suggest that the use of ABSORB BVS use in the real-world is associated with good mid-term clinical outcomes when guided by intravascular imaging.

Expansion and malapposition characteristics after bioresorbable vascular scaffold implantation.

OBJECTIVES: This study sought to investigate the postdeployment expansion and malapposition characteristics of the bioresorbable vascular scaffold (BVS) in real-world practice. BACKGROUND: The material construct of the BVS precludes overexpansion, with consequent potential for scaffold underexpansion and malapposition. In metallic stents, these features are associated with an increased risk of adverse events, including stent thrombosis. The postdeployment characteristics of the BVS are yet to be described outside clinical trials, where implantation occurred in straightforward lesion subsets. METHODS: Data from 25 patients undergoing BVS implantation were analyzed. Optical coherence tomography (OCT) was performed both before and after intervention to assess plaque composition, scaffold expansion and strut apposition. Manufacturer's compliance charts were used to predict expected minimal scaffold diameter and area. RESULTS: OCT pullback (522.2 mm) was analyzed. Overall, BVS achieved 82.5 ± 8.7 and 79.8 ± 12.3% of predicted minimal stent diameter and cross-sectional area (SCA), respectively, with expansion reduced in middle third of the scaffold (central SCA 76.7 ± 10.9% vs. noncentral SCA 81.5 ± 12.7%, P < 0.0001). Improved measures of SCA were observed with 1:1 balloon:vessel predilatation (1:1 PreD 82.8 ± 9.5% vs. No 1:1 PredD 78.6 ± 13.0%, P < 0.0001). Seven thousand six hundred scaffold struts were identified, of which 470 (6.18%) were malapposed. In fibrocalcific (FCa) plaques, malapposition was observed more frequently (FCa 44.4% vs. Other plaques 7.5%, P < 0.001) and at a greater distance from the vessel wall (FCa 0.17 ± 0.10 mm vs. Other plaques 0.14 ± 0.08 mm, P = 0.002). CONCLUSIONS: In this study, BVS expansion was significantly improved by 1:1 PreD, while increased rates of malapposition was associated with FCa plaques.

Oral amiodarone provoking inferior ST elevation and unmasking Brugada-like electrocardiogram feature.

A woman presented with broad complex tachycardia. She was converted to sinus rhythm with intravenous amiodarone and continued on oral amiodarone. The amiodarone was stopped 3 weeks later as she was pregnant. Electrocardiogram (ECG) then revealed coved-type ST elevation in C1, suggestive of Brugada syndrome, and widespread inferior ST elevation. Electrocardiogram several months later showed resolution of inferior ST elevation.

Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study.

OBJECTIVES: The purpose of this study was to determine whether thin-capped fibroatheromata (TCFA) identified by virtual histology intravascular ultrasound (VH-IVUS) are associated with major adverse cardiac events (MACE) on individual plaque or whole patient analysis. BACKGROUND: Post-mortem studies have identified TCFA as the substrate for most myocardial infarctions. However, little is known about the natural history of individual TCFA and their link with MACE. VH-IVUS provides a method of identifying plaques in vivo that are similar (although not identical) to histologically defined TCFA, and has been validated in human atherectomy and post-mortem studies. METHODS: One hundred seventy patients with stable angina or troponin-positive acute coronary syndrome referred for percutaneous coronary intervention (PCI) were prospectively enrolled and underwent 3-vessel VH-IVUS pre-PCI and also post-PCI in the culprit vessel. MACE consisted of death, myocardial infarction, or unplanned revascularization. RESULTS: In all, 30,372 mm of VH-IVUS were analyzed. Eighteen MACE occurred in 16 patients over a median follow-up of 625 days (interquartile range: 463 to 990 days); 1,096 plaques were classified, and 19 lesions resulted in MACE (13 nonculprit lesions and 6 culprit lesions). Nonculprit lesion factors associated with nonrestenotic MACE included VHTCFA (hazard ratio [HR]: 7.53, p = 0.038) and plaque burden >70% (HR: 8.13, p = 0.011). VHTCFA (HR: 8.16, p = 0.007), plaque burden >70% (HR: 7.48, p < 0.001), and minimum luminal area <4 mm(2) (HR: 2.91, p = 0.036) were associated with total MACE. On patient-based analysis, the only factor associated with nonrestenotic MACE was 3-vessel noncalcified VHTCFA (HR: 1.79, p = 0.004). CONCLUSIONS: VH-IVUS TCFA was associated with nonrestenotic and total MACE on individual plaque analysis, and noncalcified VHTCFA was associated with nonrestenotic and total MACE on whole-patient analysis, demonstrating that VH-IVUS can identify plaques at increased risk of subsequent events. The preservation of the association between VHTCFA and MACE despite various analyses emphasizes its biological importance.

Leukocyte telomere length is associated with high-risk plaques on virtual histology intravascular ultrasound and increased proinflammatory activity.

OBJECTIVE: Leukocyte telomere length (LTL), a marker of cellular senescence, is inversely associated with cardiovascular events. However, whether LTL reflects plaque extent or unstable plaques, and the mechanisms underlying any association are unknown. METHODS AND RESULTS: One hundred seventy patients with stable angina or acute coronary syndrome referred for percutaneous coronary intervention underwent 3-vessel virtual histology intravascular ultrasound; 30 372 mm of intravascular ultrasound pullback and 1096 plaques were analyzed. LTL was not associated with plaque volume but was associated with calcified thin-capped fibroatheroma (OR, 1.24; CI, 1.01-1.53; P=0.039) and total fibroatheroma numbers (OR, 1.19; CI, 1.02-1.39; P=0.027). Monocytes from coronary artery disease patients showed increased secretion of proinflammatory cytokines. To mimic leukocyte senescence, we disrupted telomeres and binding and expression of the telomeric protein protection of telomeres protein-1, inducing DNA damage. Telomere disruption increased monocyte secretion of monocyte chemoattractant protein-1, IL-6, and IL-1ß and oxidative burst, similar to that seen in coronary artery disease patients, and lymphocyte secretion of IL-2 and reduced lymphocyte IL-10. CONCLUSIONS: Shorter LTL is associated with high-risk plaque morphology on virtual histology intravascular ultrasound but not total 3-vessel plaque burden. Monocytes with disrupted telomeres show increased proinflammatory activity, which is also seen in coronary artery disease patients, suggesting that telomere shortening promotes high-risk plaque subtypes by increasing proinflammatory activity.

Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques.

Although monocytes/macrophages are considered important in atherogenesis, their role in established plaques is unclear. For example, macrophage content is associated with plaque instability, but their loss through cell death is observed at sites of plaque rupture. To examine the role of monocytes/macrophages in atherosclerosis, we developed CD11b-diphtheria toxin (DT) receptor (DTR) transgenic mice, whereby administration of DT selectively kills monocytes/macrophages. DT treatment reduced peripheral blood monocytes and tissue macrophages and inhibited macrophage function in CD11b-DTR mice and apolipoprotein E-null (apoE(-/-)) mice transplanted with CD11b-DTR bone marrow. In atherogenesis experiments, DT markedly reduced plaque development and altered plaque composition, reducing collagen content and necrotic core formation. In mice with established plaques, acute DT treatment induced macrophage apoptosis and reduced macrophage content but did not induce plaque inflammation, thrombosis, or rupture. Furthermore, despite a 50% reduction in monocytes, chronic DT treatment of these mice did not alter plaque extent or composition, most likely because of ongoing recruitment/proliferation of monocytes with recovery of macrophage content. We conclude that monocytes/macrophages are critical to atherogenesis, but established plaques are more resistant to reductions in monocytes.

Endogenous p53 protects vascular smooth muscle cells from apoptosis and reduces atherosclerosis in ApoE knockout mice.

Recent studies have indicated that the tumor suppressor gene p53 limits atherosclerosis in animal models; p53 expression is also increased in advanced human plaques compared with normal vessels, where it may induce growth arrest and apoptosis. However, controversy exists as to the role of endogenous levels of p53 in different cell types that comprise plaques. We examined atherosclerotic plaque development and composition in brachiocephalic arteries and aortas of p53-/-/ApoE-/- mice versus wild type p53 controls. p53-/- mice demonstrated increased aortic plaque formation, with increased rates of cell proliferation and reduced rates of apoptosis in brachiocephalic arteries. Although most proliferating cells were monocyte/macrophages, apoptotic cells were both vascular smooth muscle cells (VSMCs) and macrophages. Transplant of p53 bone marrow to p53-/-/ApoE-/- mice reduced aortic plaque formation and cell proliferation in brachiocephalic plaques, but also markedly reduced apoptosis. To examine p53 regulation of these processes, we studied proliferation and apoptosis in macrophages, bone marrow stromal cells and VSMCs cultured from these mice. Although endogenous p53 promoted apoptosis in macrophages, it protected VSMCs and stromal cells from death, a hitherto unknown function in these cells, in part by inhibiting DNA damage response enzymes. p53 also inhibited stromal cell expression of VSMC markers. We conclude that endogenous levels of p53 protect VSMCs and stromal cells against apoptosis, while promoting apoptosis in macrophages, and protect against atherosclerosis development.