Stephen P. Hoole

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.

DPP-4 Inhibition by Sitagliptin Improves the Myocardial Response to Dobutamine Stress and Mitigates Stunning in a Pilot Study of Patients With Coronary Artery Disease

Background—Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted postprandially that promotes myocardial glucose uptake. The active amide GLP-1 (7-36) is degraded by the enzyme DPP-4, and drugs that inhibit this enzyme (such as sitagliptin) have been introduced to treat type 2 diabetes. We assessed the hypothesis that increasing the plasma concentration of GLP-1 by DPP-4 inhibition would protect the heart from ischemic left ventricular (LV) dysfunction during dobutamine stress echocardiography in patients with coronary artery disease. Methods and Results—Fourteen patients with coronary artery disease and preserved LV function awaiting revascularization were studied. After either a single dose of 100 mg sitagliptin or placebo, 75 g of glucose was given orally to promote GLP-1 secretion and dobutamine stress echocardiography was conducted with tissue Doppler imaging at rest, peak stress, and 30 minutes. After sitagliptin, plasma GLP-1 (7-36) was increased at peak stress (16.5±10.7 versus 9.7±8.7 pg/mL; P=0.003) and in recovery (12.4±5.5 versus 9.0±5.5 pg/mL; P=0.01), and the LV response to stress was enhanced (ejection fraction, 72.6±7.2 versus 63.9±7.9%, P=0.0001; mitral annular systolic velocity, 12.54±3.18 versus 11.49±2.52 cm/s; P=0.0006). DPP-4 inhibition also improved LV regional function in the 12 paired nonapical segments assessed by peak systolic tissue Doppler (velocity, 10.56±4.49 versus 9.81±4.26 cm/s, P=0.002; strain, −15.9±6.3 versus −14.6±6.6%, P=0.01; strain rate, −2.04±1.04 versus −1.75±0.98 s−1, P=0.0003). This was predominantly due to a cardioprotective effect on ischemic segments (velocity in ischemic segments, 9.77±4.18 versus 8.74±3.87, P=0.007; velocity in nonischemic segments, 11.51±4.70 versus 11.14±4.38, P=0.14). In recovery, sitagliptin attenuated the postischemic stunning seen after the control study. Conclusions—The augmentation of GLP-1 (7-36) by inhibition of DPP-4 improves global and regional LV performance in response to stress and mitigates postischemic stunning in humans with coronary artery disease. Clinical Trial Registration—URL: http://www.isrctn.org. Unique identifier: ISRCTN78649100.

Remote Ischemic Preconditioning Improves Outcome at 6 Years After Elective Percutaneous Coronary Intervention The CRISP Stent Trial Long-term Follow-up

Background—Postprocedural myocardial infarction (type 4a) has been shown to be an adverse prognostic indicator after elective percutaneous coronary intervention (PCI). The Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) study demonstrated that remote ischemic preconditioning reduced procedural symptoms, ECG ST-segment deviation, and cardiac troponin I release after elective PCI and reduced the major adverse cardiac and cerebral event (MACCE) rate at 6 months. We were interested to confirm if this early benefit in MACCE rate in the remote ischemic preconditioning group was sustained long-term. Methods and Results—Patients were telephoned by researchers blinded to the randomization details. MACCE, defined as all-cause mortality, nonfatal myocardial infarction, transient ischemic attack or stroke, and heart failure requiring hospital admission, were adjudicated by case note and national database review. One hundred ninety-two (89.3%) of the 225 patients with elective PCI randomized in the original study were available for long-term follow-up (mean time to event or last follow-up: 1579.7±603.6 days). There were a total of 59 (30.7%) MACCEs. Patients with an MACCE had a higher mean cardiac troponin I after PCI (±SD): 2.07±6.99 versus 0.91±2.07 ng/mL (P=0.05). The MACCE rate at 6 years remained lower in the remote ischemic preconditioning group (hazard ratio, 0.58; 95% confidence interval, 0.35–0.97; P=0.039; absolute risk reduction=0.13 and number needed to treat=8 to prevent the MACCE at 6 years). Conclusions—Remote ischemic preconditioning reduces the incidence of postprocedural cardiac troponin I after elective PCI and confers an MACCE-free survival benefit at both short- and long-term follow-up. Clinical Trial Registration—URL: http://www.ukcrn.org.uk. Unique identifier: UKCRN 4074

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.

Atherosclerotic plaque composition and classification identified by coronary computed tomography: assessment of computed tomography-generated plaque maps compared with virtual histology intravascular ultrasound and histology.

Background— Computed tomography (CT) is used routinely for coronary angiography, and higher-risk features of plaques can also be identified. However, the ability of CT to discriminate individual plaque components and classify plaques according to accepted histological definitions is unknown. Methods and Results— We first determined CT attenuation ranges for individual plaque components using combined in vivo CT coregistered with virtual histology intravascular ultrasound (VH-IVUS) in 108 plaques from 57 patients. Comparison with contrast attenuation created plaque/contrast attenuation ratios that were significantly different for each component. In a separate validation cohort of 47 patients, these Plaque Maps correlated significantly with VH-IVUS–determined plaque component volumes (necrotic core: r=0.41, P=0.002; fibrous plaque: r=0.54, P<0.001; calcified plaque: r=0.59, P<0.001; total plaque: r=0.62, P<0.001). We also assessed VH-IVUS and CT Plaque Maps against coregistered histology in 72 (VH-IVUS) and 87 (CT) segments from 8 postmortem coronary arteries. The diagnostic accuracy of CT to detect calcified plaque (83% versus 92%), necrotic core (80% versus 65%), and fibroatheroma (80% versus 79%) was comparable with VH-IVUS. However, although VH-IVUS could identify thin-cap fibroatheromas (TCFA) with a diagnostic accuracy of between 74% and 82% (depending on the TCFA definition used), the spatial resolution of CT prevented direct identification of TCFA. Conclusions— CT-derived Plaque Maps based on contrast-adjusted attenuation ranges can define individual plaque components with a similar accuracy to VH-IVUS ex vivo. However, coronary CT Plaque Maps could not reliably classify plaques and identify TCFA, such that high-risk plaques may be misclassified or overlooked.

Coronary Plaque Structural Stress Is Associated With Plaque Composition and Subtype and Higher in Acute Coronary Syndrome The BEACON I (Biomechanical Evaluation of Atheromatous Coronary Arteries) Study

Background—Atherosclerotic plaques underlying most myocardial infarctions have thin fibrous caps and large necrotic cores; however, these features alone do not reliably identify plaques that rupture. Rupture occurs when plaque structural stress (PSS) exceeds mechanical strength. We examined whether PSS could be calculated in vivo based on virtual histology (VH) intravascular ultrasound and whether PSS varied according to plaque composition, subtype, or clinical presentation. Methods and Results—A total of 4429 VH intravascular ultrasound frames from 53 patients were analyzed, identifying 99 584 individual plaque components. PSS was calculated by finite element analysis in whole vessels, in individual plaques, and in higher-risk regions (plaque burden ≥70%, mean luminal area ⩽4 mm2, noncalcified VH-defined thin-cap fibroatheroma). Plaque components including total area/arc of calcification (R2=0.33; P<0.001 and R2=0.28; P<0.001) and necrotic core (R2=0.18; P<0.001 and R2=0.15; P<0.001) showed complex, nonlinear relationships with PSS. PSS was higher in noncalcified VH-defined thin-cap fibroatheroma compared with thick-cap fibroatheromas (median [Q1–Q3], 8.44 [6.97–10.64] versus 7.63 [6.37–9.68]; P=0.002). PSS was also higher in patients with an acute coronary syndrome, where mean luminal area ⩽4 mm2 (8.24 [7.06–9.93] versus 7.72 [6.33–9.34]; P=0.03), plaque burden ≥70% (9.18 [7.44–10.88] versus 7.93 [6.16–9.46]; P=0.02), and in noncalcified VH-defined thin-cap fibroatheroma (9.23 [7.33–11.44] versus 7.65 [6.45–8.62]; P=0.02). Finally, PSS increased the positive predictive value for VH intravascular ultrasound to identify clinical presentation. Conclusions—Finite element analysis modeling demonstrates that structural stress is highly variable within plaques, with increased PSS associated with plaque composition, subtype, and higher-risk regions in patients with acute coronary syndrome. PSS may represent a novel tool to analyze the dynamic behavior of coronary plaques with the potential to improve prediction of plaque rupture.

Chronic Dipeptidyl Peptidase-4 Inhibition With Sitagliptin Is Associated With Sustained Protection Against Ischemic Left Ventricular Dysfunction in a Pilot Study of Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease

Background—The incretin hormone, glucagon-like peptide-1, promotes myocardial glucose uptake and may improve myocardial tolerance to ischemia. Endogenous glucagon-like peptide-1 (7–36) is augmented by pharmacological inhibition of dipeptidyl peptidase-4. We investigated whether chronic dipeptidyl peptidase-4 inhibition by sitagliptin protected against ischemic left ventricular dysfunction during dobutamine stress in patients with type 2 diabetes mellitus and coronary artery disease. Methods and Results—A total of 19 patients with type 2 diabetes mellitus underwent dobutamine stress echocardiography with tissue Doppler imaging on 2 separate occasions: the first (control) while receiving oral hypoglycemic agents, and the second after the addition of sitagliptin (100 mg once daily) for ≈4 weeks. Sitagliptin increased plasma glucagon-like peptide-1 (7–36) levels and, at peak stress, enhanced both global (ejection fraction, 70.5±7.0 versus 65.7±8.0%; P<0.0001; mitral annular systolic velocity, 11.7±2.6 versus 10.9±2.3 cm/s; P=0.01) and regional left ventricular function, assessed by peak systolic velocity and strain rate in 12 paired, nonapical segments. This was predominantly because of a cardioprotective effect on ischemic segments (strain rate in ischemic segments, −2.27±0.65 versus −1.98±0.58 s−1; P=0.001), whereas no effect was seen in nonischemic segments (−2.19±0.48 versus −2.18±0.54 s−1; P=0.87). At 30 minutes recovery, dipeptidyl peptidase-4 inhibition mitigated the postischemic stunning seen in the control scan. Conclusions—The addition of dipeptidyl peptidase-4 inhibitor therapy with sitagliptin to the treatment regime of patients with type 2 diabetes mellitus and coronary artery disease is associated with a sustained improvement in myocardial performance during dobutamine stress and a reduction in postischemic stunning. Clinical Trial Registration—URL: http://www.isrctn.org. Unique identifier ISRCTN61646154.

Right ventricular dysfunction in chronic thromboembolic obstruction of the pulmonary artery: a pressure-volume study using the conductance catheter

Pressure-volume loops describe dynamic ventricular performance, relevant to patients with and at risk of pulmonary hypertension. We used conductance catheter-derived pressure-volume loops to measure right ventricular (RV) mechanics in patients with chronic thromboembolic pulmonary arterial obstruction at different stages of pathological adaptation. Resting conductance catheterization was performed in 24 patients: 10 with chronic thromboembolic pulmonary hypertension (CTEPH), 7 with chronic thromboembolic disease without pulmonary hypertension (CTED), and 7 controls. To assess the validity of conductance measurements, RV volumes were compared in a subset of 8 patients with contemporaneous cardiac magnetic resonance (CMR). Control, CTED, and CTEPH groups showed different pressure-volume loop morphology, most notable during systolic ejection. Prolonged diastolic relaxation was seen in patients with CTED and CTEPH [tau = 56.2 ± 6.7 (controls) vs. 69.7 ± 10.0 (CTED) vs. 67.9 ± 6.2 ms (CTEPH), P = 0.02]. Control and CTED groups had lower afterload (Ea) and contractility (Ees) compared with the CTEPH group (Ea = 0.30 ± 0.10 vs. 0.52 ± 0.24 vs. 1.92 ± 0.70 mmHg/ml, respectively, P < 0.001) (Ees = 0.44 ± 0.20 vs. 0.59 ± 0.15 vs. 1.13 ± 0.43 mmHg/ml, P < 0.01) with more efficient ventriculoarterial coupling (Ees/Ea = 1.46 ± 0.30 vs. 1.27 ± 0.36 vs. 0.60 ± 0.18, respectively, P < 0.001). Stroke volume assessed by CMR and conductance showed closest agreement (mean bias +9 ml, 95% CI -1 to +19 ml) compared with end-diastolic volume (+48 ml, -16 to 111 ml) and end-systolic volume (+37 ml, -21 to 94 ml). RV conductance catheterization detects novel alteration in pressure-volume loop morphology and delayed RV relaxation in CTED, which distinguish this group from controls. The observed agreement in stroke volume assessed by CMR and conductance suggests RV mechanics are usefully measured by conductance catheter in chronic thromboembolic obstruction.

Expansion and malapposition characteristics after bioresorbable vascular scaffold implantation

This study sought to investigate the postdeployment expansion and malapposition characteristics of the bioresorbable vascular scaffold (BVS) in real‐world practice.

Direct Comparison of Virtual-Histology Intravascular Ultrasound and Optical Coherence Tomography Imaging for Identification of Thin-Cap Fibroatheroma

Background—Although rupture of thin-cap fibroatheroma (TCFA) underlies most myocardial infarctions, reliable TCFA identification remains challenging. Virtual-histology intravascular ultrasound (VH-IVUS) and optical coherence tomography (OCT) can assess tissue composition and classify plaques. However, direct comparisons between VH-IVUS and OCT are lacking and it remains unknown whether combining these modalities improves TCFA identification. Methods and Results—Two hundred fifty-eight regions-of-interest were obtained from autopsied human hearts, with plaque composition and classification assessed by histology and compared with coregistered ex vivo VH-IVUS and OCT. Sixty-seven regions-of-interest were classified as fibroatheroma on histology, with 22 meeting criteria for TCFA. On VH-IVUS, plaque (10.91±4.82 versus 8.42±4.57 mm2; P=0.01) and necrotic core areas (1.59±0.99 versus 1.03±0.85 mm2; P=0.02) were increased in TCFA versus other fibroatheroma. On OCT, although minimal fibrous cap thickness was similar (71.8±44.1 &mgr;m versus 72.6±32.4; P=0.30), the number of continuous frames with fibrous cap thickness ⩽85 &mgr;m was higher in TCFA (6.5 [1.75–11.0] versus 2.0 [0.0–7.0]; P=0.03). Maximum lipid arc on OCT was an excellent discriminator of fibroatheroma (area under the curve, 0.92; 95% confidence interval, 0.87–0.97) and TCFA (area under the curve, 0.86; 95% confidence interval, 0.81–0.92), with lipid arc ≥80° the optimal cut-off value. Using existing criteria, the sensitivity, specificity, and diagnostic accuracy for TCFA identification was 63.6%, 78.1%, and 76.5% for VH-IVUS and 72.7%, 79.8%, and 79.0% for OCT. Combining VH-defined fibroatheroma and fibrous cap thickness ⩽85 &mgr;m over 3 continuous frames improved TCFA identification, with diagnostic accuracy of 89.0%. Conclusions—Both VH-IVUS and OCT can reliably identify TCFA, although OCT accuracy may be improved using lipid arc ≥80° and fibrous cap thickness ⩽85 &mgr;m over 3 continuous frames. Combined VH-IVUS/OCT imaging markedly improved TCFA identification.