Sarah C. Clarke

Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics.

Although a wide range of risk factors for coronary heart disease have been identified from population studies, these measures, singly or in combination, are insufficiently powerful to provide a reliable, noninvasive diagnosis of the presence of coronary heart disease. Here we show that pattern-recognition techniques applied to proton nuclear magnetic resonance (1H-NMR) spectra of human serum can correctly diagnose not only the presence, but also the severity, of coronary heart disease. Application of supervised partial least squares-discriminant analysis to orthogonal signal-corrected data sets allows >90% of subjects with stenosis of all three major coronary vessels to be distinguished from subjects with angiographically normal coronary arteries, with a specificity of >90%. Our studies show for the first time a technique capable of providing an accurate, noninvasive and rapid diagnosis of coronary heart disease that can be used clinically, either in population screening or to allow effective targeting of treatments such as statins.

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.

Proton NMR analysis of plasma is a weak predictor of coronary artery disease

Multivariate analysis of 1H-NMR spectra of blood sera was reported previously to predict angiographically defined advanced coronary artery disease (CAD) with >90% accuracy and specificity. The analysis depended mainly on the major lipid regions of the spectra, but many variables, including gender and drug treatment, affect lipid composition and are potential confounders. We have determined the predictive power of the same methodology for angiographically defined CAD using plasma samples from groups of male patients, classified by statin treatment, who had normal coronary arteries (NCAs) or CAD. Predictions for NCA and CAD groups were only 80.3% correct for patients not treated with statins and 61.3% for treated patients, compared with random correct predictions of 50%. A confidence limit of >99% was achieved for 36.2% of predictions for untreated groups and 6.2% for treated groups. Detection of CAD by 1H-NMR with >99% confidence was therefore very weak compared with angiography.

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.

Percutaneous myocardial laser revascularization in patients with refractory angina pectoris

This study aimed to determine the safety and efficacy of percutaneous myocardial laser revascularization (PMLR). Seventy-three patients with stable angina pectoris (class III or IV) who were unsuitable for conventional revascularization and had evidence of reversible ischemia by thallium-201 scintigraphy, ejection fraction of > or =25%, and myocardial wall thickness > or =8 mm were randomized to optimal medical therapy alone (n = 37) or PMLR with optimal medical therapy (n = 36). Patients were followed up at 3, 6, and 12 months. The primary end point was exercise time. Secondary end points included angina scores, left ventricular ejection fraction, quality of life, changes in medical therapy, and hospitalizations. All 36 patients randomized to PMLR underwent the procedure successfully with no periprocedure deaths. One patient developed sustained ventricular tachycardia that required electrical cardioversion, and 1 patient developed cardiac tamponade that required surgical drainage. At 12 months, exercise times improved by 109 seconds in the PMLR group but decreased by 62 seconds in the control group (p <0.01). Angina scores improved by 2 classes in 36% of PMLR-treated patients at 12 months compared with 0% of the control patients (p <0.01). We conclude that PMLR is a relatively safe procedure that provides patients with symptomatic angina relief and improvement in exercise capacity and quality of life.

Bacterial endocarditis complicating body art

Increasing numbers of patients are living with congenital heart disease at a time when body art is growing in popularity. We present a case of subacute bacterial endocarditis following repeated tattooing in a patient with known valvular heart disease. This case highlights the importance of education of patients with structural heart disease to the potential risks of such procedures, particularly at a time when endocarditis prophylaxis protocols are being revised.

Serial assessment of the index of microcirculatory resistance during primary percutaneous coronary intervention comparing manual aspiration catheter thrombectomy with balloon angioplasty (IMPACT study): a randomised controlled pilot study

Objective Utilising a novel study design, we evaluated serial measurements of the index of microcirculatory resistance (IMR) in patients undergoing primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) to assess the impact of device therapy on microvascular function, and determine what proportion of microvascular injury is related to the PPCI procedure, and what is an inevitable consequence of STEMI. Design 41 patients undergoing PPCI for STEMI were randomised to balloon angioplasty (BA, n=20) or manual thrombectomy (MT, n=21) prior to stenting. Serial IMR measurements, corrected for collaterals, were recorded at baseline and at each stage of the procedure. Microvascular obstruction (MVO) and infarct size at 24 h and 3 months were measured by troponin and cardiac MRI (CMR). Results IMR did not change significantly following PPCI, but patients with lower IMR values (<32, n=30) at baseline had a significant increase in IMR following PPCI (baseline: 21.2±7.9 vs post-stent: 33.0±23.7, p=0.01) attributable to prestent IRA instrumentation (baseline: 21.7±8.0 vs post-BA or MT: 36.9±25.9, p=0.006). Post-stent IMR correlated with early MVO on CMR (p=0.01). There was no significant difference in post-stent IMR, presence of early MVO or final infarct size between patients with BA and patients treated with MT. Conclusions Patients with STEMI and less microcirculatory dysfunction may be susceptible to acute iatrogenic microcirculatory injury from prestent coronary devices. MT did not appear to be superior to BA in maintaining microcirculatory integrity when the guide wire partially restores IRA flow during PPCI. Trial registration number ISRCTN31767278.