Michael O'Sullivan

Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective, randomized control trial.

Background— Myocyte necrosis as a result of elective percutaneous coronary intervention (PCI) occurs in approximately one third of cases and is associated with subsequent cardiovascular events. This study assessed the ability of remote ischemic preconditioning (IPC) to attenuate cardiac troponin I (cTnI) release after elective PCI. Methods and Results— Two hundred forty-two consecutive patients undergoing elective PCI with undetectable preprocedural cTnI were recruited. Subjects were randomized to receive remote IPC (induced by three 5-minute inflations of a blood pressure cuff to 200 mm Hg around the upper arm, followed by 5-minute intervals of reperfusion) or control (an uninflated cuff around the arm) before arrival in the catheter laboratory. The primary outcome was cTnI at 24 hours after PCI. Secondary outcomes included renal dysfunction and major adverse cardiac and cerebral event rate at 6 months. The median cTnI at 24 hours after PCI was lower in the remote IPC compared with the control group (0.06 versus 0.16 ng/mL; P=0.040). After remote IPC, cTnI was <0.04 ng/mL in 44 patients (42%) compared with 24 in the control group (24%; P=0.01). Subjects who received remote IPC experienced less chest discomfort (P=0.0006) and ECG ST-segment deviation (P=0.005) than control subjects. At 6 months, the major adverse cardiac and cerebral event rate was lower in the remote IPC group (4 versus 13 events; P=0.018). Conclusion— Remote IPC reduces ischemic chest discomfort during PCI, attenuates procedure-related cTnI release, and appears to reduce subsequent cardiovascular events.

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.

Mechanisms of angioplasty and stent restenosis: implications for design of rational therapy

Restenosis after angioplasty or stenting remains the major limitation of both procedures. A vast array of drug therapies has been used to prevent restenosis, but they have proven to be predominantly unsuccessful. Recent trends in drug therapy have attempted to refine the molecular and biological targets of therapy, based on the assumption that a single biological process or molecule is critical to restenosis. In contrast, both stenting and brachytherapy, which are highly nonspecific, can successfully reduce restenosis after angioplasty or stenting, respectively. This review examines the biology of both angioplasty and stent stenosis, focussing on human studies. We also review the landmark human trials that have definitively proven successful therapies, such as stenting and brachytherapy. We suggest that the successful trials of stenting and brachytherapy and the failure of other treatments have highlighted the shortcomings of conventional animal models of arterial intervention, and gaps in our knowledge of human disease. In contrast to arguments advocating gene therapy, these studies suggest that the most likely successful drug therapy will have a wide therapeutic range, targeting as many of the components or biological processes contributing to restenosis as possible.

A Pilot Study to Assess Whether Glucagon-Like Peptide-1 Protects the Heart From Ischemic Dysfunction and Attenuates Stunning After Coronary Balloon Occlusion in Humans

Background— The incretin hormone glucagon-like peptide-1 (GLP-1) has been shown to have cardioprotective properties in animal models of ischemia and infarction due to promotion of myocardial glucose uptake and suppression of apoptosis. We investigated whether GLP-1 protected the heart from dysfunction caused by supply ischemia during percutaneous coronary intervention (PCI). Methods and Results— Twenty patients with normal left ventricular (LV) function and single-vessel coronary disease within the left anterior descending artery undergoing elective PCI were studied. A conductance catheter was placed into the LV through the femoral artery, and pressure-volume loops were recorded at baseline and during a 1-minute low-pressure balloon occlusion at the site of the stenosis. The patients were randomized to receive an infusion of either GLP-1(7–36) amide at 1.2 pmol/kg per minute or saline immediately after the first balloon occlusion. Coronary balloon occlusion caused LV stunning in the control group with cumulative LV dysfunction on subsequent occlusion that was not seen in the GLP-1 group. GLP-1 improved recovery of LV systolic and diastolic function at 30 minutes after balloon occlusion compared with control (delta dP/dtmax from baseline, −1.6% versus −12.2%; P=0.02) and reduced the LV dysfunction after the second balloon occlusion (delta dP/dtmax, −13.1% versus −25.3%; P=0.01). Conclusions— In this pilot study, infusion of GLP-1 has been demonstrated to reduce ischemic LV dysfunction after supply ischemia during coronary balloon occlusion in humans and mitigates stunning. The findings require confirmation in a larger scale clinical trial. Clinical Trial Registration— URL: http://www.isrctn.org. Unique identifier: ISRCTN 77442023.

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-1&bgr; and oxidative burst, similar to that seen in coronary artery disease patients, and lymphocyte secretion of IL-2 and reduced lymphocyte IL-10. Conclusion— 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.

Remote ischaemic pre‐conditioning does not attenuate ischaemic left ventricular dysfunction in humans

Remote ischaemic pre‐conditioning (RIPC) reduces distant tissue ischaemia reperfusion injury. We tested the hypothesis that RIPC would protect the left ventricle (LV) from ischaemic dysfunction and stunning.

Remote Ischemic Preconditioning Stimulus Does Not Reduce Microvascular Resistance or Improve Myocardial Blood Flow in Patients Undergoing Elective Percutaneous Coronary Intervention

Introduction: Remote ischemic preconditioning (RIPC) may limit myocardial infarction by improving microvascular function and maintaining myocardial blood flow. We hypothesized that a RIPC stimulus would reduce coronary microvascular resistance and improve coronary blood flow during elective percutaneous coronary intervention (PCI). Method: We prospectively recruited 54 patients with multi-vessel disease (MVD = 32) or single vessel disease awaiting elective PCI. Patients with MVD had non-target vessel (NTV) index of micro-circulatory resistance (IMR) determined, before and after target vessel (TV) PCI (cardiac RIPC). The effect of arm RIPC on serial microvascular resistance (Rp) was assessed in patients with single vessel disease. Results: TV balloon occlusion did not alter the NTV IMR: 16.5 (12.4) baseline vs. 17.6 (11.6) post cardiac RIPC, P = 0.65 or hyperaemic transit time. Arm RIPC did not alter R p in patients with single vessel disease: Rp, mmHg.cm-1.s -1: 3.5 (1.9) baseline vs. 4.1 (3.0) post arm RIPC, P = 0.19 and coronary flow velocity remained constant. Conclusion: RIPC stimuli during elective PCI do not affect coronary microvascular resistance or coronary flow in humans.

Stunning and cumulative left ventricular dysfunction occurs late after coronary balloon occlusion in humans insights from simultaneous coronary and left ventricular hemodynamic assessment.

OBJECTIVES We aimed to investigate whether left ventricular (LV) stunning could be detected late after coronary occlusion when coronary flow has normalized. BACKGROUND Stunning and cumulative LV dysfunction after ischemia reperfusion has been clearly demonstrated in animal models but has been refuted in several angioplasty models in humans. However, these studies have assessed LV function early, during the reactive hyperemic phase, which might have augmented LV function. METHODS We recruited 20 male subjects with single-vessel, type A coronary disease, and normal ventricular function. We simultaneously measured LV function with a conductance catheter and coronary flow velocity with a Combowire (Volcano Therapeutics, Inc., Rancho Cordova, California) at baseline (BL), for 30 s after a low-pressure coronary balloon occlusion for 1 min and again after 30 min, before a second balloon occlusion. RESULTS Stunning was detected at 30 min after a 1-min balloon occlusion: stroke volume (ml) BL1: 88.4 (22.8) versus BL2: 79.4 (24.0), p = 0.04; tau (ms) BL1: 49.8 (9.0) versus BL2: 52.5 (8.9), p = 0.02, despite full recovery of coronary average peak velocity (p = 0.62). A second balloon occlusion caused cumulative LV dysfunction: stroke volume (ml) BO1: 77.3 (34.6) versus BO2 64.9 (22.9), p = 0.01. Reactive hyperemia significantly augmented early recovery systolic function: dP/dt max 30 s: +5.8% versus 30 min - 5.4%, p = 0.0009. CONCLUSIONS Coronary occlusion for 1-min results in late stunning and cumulative LV dysfunction after 30 min. Reactive hyperemia augments stunned LV systolic function in early recovery.

Primary coronary microvascular dysfunction and poor coronary collaterals predict post-percutaneous coronary intervention cardiac necrosis

BackgroundAn elevation in cardiac troponin-I (cTnI) after elective percutaneous coronary intervention (PCI) is because of cardiac necrosis and has prognostic implications. Primary microvascular dysfunction, evident before PCI, and paucity of coronary collaterals at baseline may influence cTnI. MethodsWe selected 22 patients awaiting elective PCI for a single-vessel, type-A coronary stenosis, with normal left ventricular function and a normal preprocedure cTnI. Intracoronary pressure and Doppler flow were measured during coronary balloon occlusion to derive microvascular resistance: Rp=[Pd(occl)–Pv]/APVoccl and collateral resistance: Rcoll=[Pa–Pd(occl)]/APVoccl, at each stage of PCI, where Pa is mean aortic pressure, Pv is central venous pressure, Pd(occl) is mean distal pressure, Rp is coronary microvascular resistance, Rcoll is coronary collateral resistance, and APVoccl is average peak velocity during coronary balloon occlusion. The resistance indices were compared with postprocedural cTnI levels measured at 24 h. ResultsThere was a relationship between baseline Rp before PCI and elevated plasma cTnI levels at 24 h. Mean (SEM) Rp (mmHg/cm/s) increased for each cTnI tertile: T1 (mean cTnI 0.04 ng/ml): 1.3 (0.3), T2 (mean cTnI 0.13 ng/ml): 3.1 (0.4), and T3 (mean cTnI 2.5 ng/ml): 4.6 (0.7) (P=0.002). Baseline Rcoll (mmHg/cm/s) was similarly related to cTnI result and mean values showed an increasing trend: T1: 11.1 (1.9), T2: 14.5 (2.3), and T3: 19.5 (3.4) (P=0.12). Serial coronary balloon occlusions did not significantly alter Rp (P=0.82) or recruit coronary collaterals (P=0.69). ConclusionPrimary coronary microvascular dysfunction and poor collaterals at baseline are associated with post-PCI necrosis.

Coronary collaterals provide a constant scaffold effect on the left ventricle and limit ischemic left ventricular dysfunction in humans

Coronary collaterals preserve left ventricular (LV) function during coronary occlusion by reducing myocardial ischemia and may directly influence LV compliance. We aimed to re-evaluate the relationship between coronary collaterals, measured quantitatively with a pressure wire, and simultaneously recorded LV contractility from conductance catheter data during percutaneous coronary intervention (PCI) in humans. Twenty-five patients with normal LV function awaiting PCI were recruited. Pressure-derived collateral flow index (CFI(p)): CFI(p) = (P(w) - P(v))/(P(a) - P(v)) was calculated from pressure distal to coronary balloon occlusion (P(w)), central venous pressure (P(v)), and aortic pressure (P(a)). CFI(p) was compared with the changes in simultaneously recorded LV end-diastolic pressure (ΔLVEDP), end-diastolic volume, maximum rate of rise in pressure (ΔLVdP/dt(max); systolic function), and time constant of isovolumic relaxation (ΔLV τ; diastolic function), measured by a LV cavity conductance catheter. Measurements were recorded at baseline and following a 1-min coronary occlusion and were duplicated after a 30-min recovery period. There was significant LV diastolic dysfunction following coronary occlusion (ΔLVEDP: +24.5%, P < 0.0001; and ΔLV τ: +20.0%, P < 0.0001), which inversely correlated with CFI(p) (ΔLVEDP vs. CFI(p): r = -0.54, P < 0.0001; ΔLV τ vs. CFI(p): r = -0.46, P = 0.0009). Subjects with fewer collaterals had lower LVEDP at baseline (r = 0.33, P = 0.02). CFI(p) was inversely related to the coronary stenosis pressure gradient at rest (r = -0.31, P = 0.03). Collaterals exert a direct hemodynamic effect on the ventricle and attenuate ischemic LV diastolic dysfunction during coronary occlusion. Vessels with lesions of greater hemodynamic significance have better collateral supply.