18F-FDG PET/CT improves diagnostic certainty in native and prosthetic valve Infective Endocarditis over the modified Duke Criteria.

BACKGROUND: International guidance recognizes the shortcomings of the modified Duke Criteria (mDC) in diagnosing infective endocarditis (IE) when transoesophageal echocardiography (TOE) is equivocal. 18F-FDG PET/CT (PET) has proven benefit in prosthetic valve endocarditis (PVE), but is restricted to extracardiac manifestations in native disease (NVE). We investigated the incremental benefit of PET over the mDC in NVE. METHODS: Dual-center retrospective study (2010-2018) of patients undergoing myocardial suppression PET for NVE and PVE. Cases were classified by mDC pre- and post-PET, and evaluated against discharge diagnosis. Receiver Operating Characteristic (ROC) analysis and net reclassification index (NRI) assessed diagnostic performance. Valve standardized uptake value (SUV) was recorded. RESULTS: 69/88 PET studies were evaluated across 668 patients. At discharge, 20/32 had confirmed NVE, 22/37 PVE, and 19/69 patients required surgery. PET accurately re-classified patients from possible, to definite or rejected (NRI: NVE 0.89; PVE 0.90), with significant incremental benefit in both NVE (AUC 0.883 vs 0.750) and PVE (0.877 vs 0.633). Sensitivity and specificity were 75% and 92% in NVE; 87% and 86% in PVE. Duration of antibiotics and C-reactive Protein level did not impact performance. No diagnostic SUV cut-off was identified. CONCLUSION: PET improves diagnostic certainty when combined with mDC in NVE and PVE.

Diagnostic accuracy of cardiac magnetic resonance imaging in the detection and characterization of left atrial catheter ablation lesions: a multicenter experience.

INTRODUCTION: We tested the hypothesis that cardiovascular magnetic resonance (CMR) imaging can reliably distinguish the presence or absence of left atrial (LA) ablation lesions by blinded analysis of pre- and postablation imaging. METHODS: Consecutive patients at 2 centers undergoing pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation by either wide area circumferential radiofrequency ablation (WACA) or ostial ablation with a cryoballoon underwent CMR late gadolinium enhancement (LGE) imaging pre- and 3 months postablation. Imaging was anonymized for blinded analysis of (1) LGE images, and (2) a 3D fusion image with LGE projected onto a segmented LA surface. Scans were categorized using both assessment techniques separately as pre- or postablation, and if postablation, whether lesions were in an ostial or WACA distribution. RESULTS: LGE imaging was performed in 50 patients (aged 60 ± 10 years, 68% male, 24 underwent WACA and 26 had cryoablation). Sensitivity and specificity for detection of ablation lesions was 60% and 96% on LGE imaging. Sensitivity was higher using 3D fusion imaging (88%; P = 0.003). The proportion in whom lesions were both detected and the distribution correctly assessed as WACA or ostial was higher with 3D fusion imaging compared to LGE imaging (54% vs 28%; P = 0.014). There was no difference in the detection of radiofrequency ablation lesions compared to cryoablation lesions (58% vs 62%; P = 1.000). CONCLUSION: LGE imaging of atrial scar is not yet sufficiently accurate to reliably identify ablation lesions or to determine lesion distribution.

Computed tomography cardiac angiography for planning invasive angiographic procedures in patients with previous coronary artery bypass grafting.

AIMS: Invasive coronary angiography (ICA) is more complex and challenging in patients with previous coronary artery bypass grafts (CABG). Computed tomography coronary angiography (CTCA) may provide useful information prior to ICA to improve these procedures. This study aimed to see if upfront CTCA prior to coronary angiography can reduce contrast load, procedural duration, and procedural complications compared to ICA alone. METHODS AND RESULTS: This single-centre observational study included 835 patients with prior CABG undergoing invasive coronary angiography. One hundred and six patients underwent CTCA prior to ICA and were compared to 729 patients undergoing conventional coronary angiography alone (control group). No significant differences were seen between the two groups in patient demographics and procedural characteristics (number of bypass grafts), and interventional cardiologists' experience. The CTCA group had lower contrast volumes (171.3 vs 287.4 ml, p<0.0001), radiation doses (effective dose 4.6 vs 10.5 mSv, p<0.0001) and procedure times (fluorosocopy time 9.5 vs 12.6 min, p<0.0001) at the time of ICA compared to patients who did not have prior CTCA. Combined radiation doses (ICA+CTCA) versus ICA alone were similar (p=0.867) with significant reductions in overall contrast used seen in the CTCA group (p=0.005). Complete diagnostic studies were performed in all patients with prior CTCA (106 patients, 100%) compared to 543 patients (74.64%, p=<0.0001) without previous CTCA. As a result, 34 patients (4.4%) went on to have CTCA post angiography due to missed grafts. Of these, four needed further invasive angiographic assessment and subsequent coronary intervention following the CTCA scan. CONCLUSIONS: Prior CTCA improves graft detection at the time of coronary angiography and reduces the time necessary to localise graft ostium, the total procedure time, and volume of contrast media used.

Reduced peripheral skeletal muscle mass and abnormal reflex physiology in chronic heart failure.

BACKGROUND: The muscle hypothesis implicates abnormalities in peripheral muscle as a source for the stimulus to the symptoms and reflex abnormalities seen in chronic heart failure (CHF). We investigated the relationship between skeletal muscle mass (with dual-energy x-ray absorptiometry) and activation of the ergoreflex (a peripheral reflex originating in skeletal muscle sensitive to products of muscle work) in CHF patients and whether this rapport is affected by the progression of the syndrome. METHODS AND RESULTS: We assessed 107 consecutive CHF patients (mean age, 61.9+/-10.9 years; 95% male; 25 cachectics) and 24 age-matched normal subjects (mean age, 59.0+/-11.1 years; 91% male). Compared with normal subjects, patients had a higher ergoreflex (in ventilation, 6.2+/-.6.1 versus 0.6+/-0.6 L/min; P<0.0001) and a reduction in muscle mass (51.9+/-10.0 versus 60.3+/-8.8 kg; P<0.001). The ergoreflex was particularly overactive in cachectics (P<0.05), accompanied by marked muscle mass depletion (P<0.0005). In CHF, ergoreceptor hyperresponsiveness in both the arm and leg correlated with reduced muscle mass, abnormal indexes of exercise tolerance (peak V(O2), V(E)/V(CO2) slope), ejection fraction, and NYHA functional class (P<0.0001). In the cachectic population, the ventilatory response from ergoreflex to arm exercise was strongly inversely correlated with arm (r=-0.65), leg (r=-0.64), and total (r=-0.61) lean tissues (P<0.001 for all). Multivariate analysis showed that these relationships were independent of NYHA class, peak V(O2), and V(E)/V(CO2) slope. CONCLUSIONS: Depleted peripheral muscle mass is associated with ergoreflex overactivity and exercise limitation in CHF, particularly in cachectic patients. The systemic activation of the muscle reflex system in CHF may reflect progression and deterioration of the clinical syndrome.

Analytical identification of ideal pulmonary-systemic flow balance in patients with bidirectional cavopulmonary shunt and univentricular circulation: oxygen delivery or tissue oxygenation?

BACKGROUND: In the present study, we extended previous mathematical modeling work on patients with bidirectional cavopulmonary ("bidirectional Glenn") anastomosis to assess the potential utility of several descriptors of oxygen status. We set out to determine which of these descriptors best represents the overall tissue oxygenation. We also introduce a new descriptor, SO2min, defined as the lower of the superior and inferior vena cava oxygen saturations. METHODS AND RESULTS: The application of differential calculus to a model of oxygen physiology of patients with bidirectional Glenn allowed simultaneous assessment of all possible distributions of blood flow and metabolic rate between upper and lower body, across all cardiac outputs, total metabolic rates, and oxygen-carrying capacities. When total cardiac output is fixed, although it may intuitively seem best to distribute flow to maximize oxygen delivery (total, upper body, or lower body), we found that for each variable, there are situations in which its maximization seriously deprives flow to the upper or lower circulation. In contrast, maximizing SO2min always gives physiologically sensible results. If the majority of metabolism is in the upper body (typical of infancy), then oxygenation is optimized when flow distribution matches metabolic distribution. In contrast, if the majority of metabolism is in the lower body (typical of older children and during exercise), oxygenation is optimal when flows are equal. CONCLUSIONS: In patients with bidirectional cavopulmonary anastomosis, because there is a tradeoff between flow distribution and saturation, it is unwise to concentrate on maximizing oxygen delivery. Maximizing systemic venous saturations (especially SO2min) is conceptually different and physiologically preferable for tissue oxygenation.

Coronary atherosclerotic plaque burden and composition by CT angiography in Caucasian and South Asian patients with stable chest pain.

AIMS: South Asian (SA) patients are known to have an increased incidence of acute cardiovascular events compared with Caucasians. The aim of this observational study was to compare the prevalence of coronary stenoses, the amount and composition of coronary atherosclerosis in a cohort of Caucasian and SA patients with stable chest pain, in non-acute settings. METHODS AND RESULTS: The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. In 963 consecutive Caucasian and SA patients undergoing coronary computed tomography angiography, atherosclerotic plaques were quantified using a semi-automated algorithm. The vessel per cent diameter and area stenosis were measured. Plaque composition was examined from the measurement of calcified, non-calcified, and total plaque burden. There were 420 Caucasian (238 males) and 543 SA (297 males) patients. Caucasian patients were older than SA patients (54.39 ± 11.65 vs. 49.83 ± 11.03 years) and had lower prevalence of diabetes (13.13 vs. 32.41%) and hyperlipidaemia (56.90 vs. 68.51%) (all P-values <0.001). After adjusting for differences in cardiovascular risk factors, there were no differences in per cent diameter and area stenosis, and no difference in the proportions of patients with one-, two-, or three-vessel disease. There was no difference in total plaque burden; however, the per cent non-calcified plaque composition was lower in Caucasians compared with SA (80.95 vs. 90.42%; P-value <0.001). CONCLUSION: This study conducted in non-acute settings showed an ethnic difference in composition of coronary atherosclerotic plaque with lower non-calcified composition in Caucasian patients compared with SA patients, which was independent of age, diabetes, hyperlipidaemia, and the other available cardiovascular risk factors.

Renin-Angiotensin System Blockade Improves Cardiac Indices in Acromegaly Patients.

Blockade of the angiotensin-renin system, with angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), has been shown to improve cardiac outcomes following myocardial infarction and delay progression of heart failure. Acromegaly is associated with a disease-specific cardiomyopathy, the pathogenesis of which is poorly understood.The cardiac indices of patients with active acromegaly with no hypertension (Group A, n=4), established hypertension not taking ACEi/ARBs (Group B, n=4) and established hypertension taking ACEi/ARBs (Group C, n=4) were compared using cardiac magnetic imaging.Patients taking ACEi/ARBs had lower end diastolic volume index (EDVi) and end systolic volume index (ESVi) than the other 2 groups ([C] 73.24 vs. [A] 97.92 vs. [B] 101.03 ml/m2, ANOVA p=0.034, B vs. C p<0.01). Groups A and B had EDVi and ESVi values at the top of published reference range values; Group C had values in the middle of the range.Acromegaly patients on ACEi/ARBs for hypertension demonstrate improved cardiac indices compared to acromegaly patients with hypertension not taking these medications. Further studies are needed to determine if these drugs have a beneficial cardiac effect in acromegaly in the absence of demonstrable hypertension.

Characterisation of myocardial structure and function in adult-onset growth hormone deficiency using cardiac magnetic resonance.

Growth hormone (GH) can profoundly influence cardiac function. While GH excess causes well-defined cardiac pathology, fewer data are available regarding the more subtle cardiac changes seen in GH deficiency (GHD). This preliminary study uses cardiac magnetic resonance imaging (CMR) to assess myocardial structure and function in GHD. Ten adult-onset GHD patients underwent CMR, before and after 6 and 12 months of GH replacement. They were compared to 10 age-matched healthy controls and sex-matched healthy controls. Left ventricular (LV) mass index (LVMi) increased with 1 year of GH replacement (53.8 vs. 57.0 vs. 57.3 g/m2, analysis of variance p = 0.0229). Compared to controls, patients showed a trend towards reduced LVMi at baseline (51.4 vs. 60.0 g/m2, p = 0.0615); this difference was lost by 1 year of GH treatment (57.3 vs. 59.9 g/m2, p = 0.666). Significantly reduced aortic area was observed in GHD (13.2 vs. 19.0 cm2/m2, p = 0.001). This did not change with GH treatment. There were no differences in other LV parameters including end-diastolic volume index (EDVi), end-systolic volume index, stroke volume index (SVi), cardiac index and ejection fraction. There was a trend towards reduced baseline right ventricular (RV)SVi (44.1 vs. 49.1 ml/m2, p = 0.0793) and increased RVEDVi over 1 year (70.3 vs. 74.3 vs. 73.8 ml/m2, p = 0.062). Two patients demonstrated interstitial expansion, for example with fibrosis, and three myocardial ischaemia as assessed by late gadolinium enhancement and stress perfusion. The increased sensitivity of CMR to subtle cardiac changes demonstrates that adult-onset GHD patients have reduced aortic area and LVMi increases after 1 year of GH treatment. These early data should be studied in larger studies in the future.

Recommendations for accurate CT diagnosis of suspected acute aortic syndrome (AAS)--on behalf of the British Society of Cardiovascular Imaging (BSCI)/British Society of Cardiovascular CT (BSCCT).

Accurate and timely assessment of suspected acute aortic syndrome is crucial in this life-threatening condition. Imaging with CT plays a central role in the diagnosis to allow expedited management. Diagnosis can be made using locally available expertise with optimized scanning parameters, making full use of recent advances in CT technology. Each imaging centre must optimize their protocols to allow accurate diagnosis, to optimize radiation dose and in particular to reduce the risk of false-positive diagnosis that may simulate disease. This document outlines the principles for the acquisition of motion-free imaging of the aorta in this context.

Global impairment of cardiac autonomic nervous activity late after repair of tetralogy of Fallot.

BACKGROUND: Sustained ventricular tachycardia (VT) and sudden cardiac death (SCD) remain devastating late complications after repair of Tetralogy of Fallot (ToF). Although heart rate variability (HRV) and baroreflex sensitivity (BRS) are recognized as independent markers of autonomic activity and strong predictors of SCD in major cardiovascular disease, little is known about their role in patients with tetralogy. METHODS AND RESULTS: We measured HRV and BRS in 45 ToF patients (27 male, age 35+/-12 years, 26+/-7 years after repair) and 45 matched healthy controls. Subjects underwent 20 minute of resting measurements of heart rate (ECG) and noninvasive beat-to-beat blood pressure recording (Finapres), with 5 minutes of 0.1Hz controlled breathing followed by cardiac MRI. BRS was computed by spectral analysis and the sequence and controlled breathing methods. All HRV time and frequency domain variables were measured. All BRS and HRV variables were significantly reduced in patients compared with controls (P<0.001 in all). HRV tended to increase with years from repair. BRS decreased with previous palliation and increasing patient age. Both HRV and BRS decreased with pulmonary regurgitation, elevated right ventricular end systolic volumes and reduced right and left ventricular ejection fraction. Finally, there was an inverse relation between QRS duration (predictor of sustained VT and SCD) and indices of HRV but no relation with indices of BRS. CONCLUSION: There is global impairment of autonomic nervous system regulation late after repair of tetralogy with marked reduction of BRS and HRV. This seems to relate to previous surgical intervention/s, their timing and current right and left-sided hemodynamics. Reduced HRV also related to markers of sustained VT and SCD, suggesting possible common pathogenic mechanisms. Further studies are required to examine the prognostic significance of impaired BRS and HRV in these patients.

Variability of phase shift between blood pressure and heart rate fluctuations: a marker of short-term circulation control.

BACKGROUND: We postulated that the variability of the phase shift between blood pressure and heart rate fluctuation near the frequency of 0.10 Hz might be useful in assessing autonomic circulatory control. METHODS AND RESULTS: We tested this hypothesis in 4 groups of subjects: 28 young, healthy individuals; 13 elderly healthy individuals; 25 patients with coronary heart disease; and 19 patients with a planned or implanted cardioverter-defibrillator (ICD recipients). Data from 5 minutes of free breathing and at 2 different, controlled breathing frequencies (0.10 and 0.33 Hz) were used. Clear differences (P<0.001) in variability of phase were evident between the ICD recipients and all other groups. Furthermore, at a breathing frequency of 0.10 Hz, differences in baroreflex sensitivity (P<0.01) also became evident, even though these differences were not apparent at the 0.33-Hz breathing frequency. CONCLUSIONS: The frequency of 0.10 Hz represents a useful and potentially important one for controlled breathing, at which differences in blood pressure-RR interactions become evident. These interactions, whether computed as a variability of phase to define stability of the blood pressure-heart rate interaction or defined as the baroreflex sensitivity to define the gain in heart rate response to blood pressure changes, are significantly different in patients at risk for sudden arrhythmic death. In young versus older healthy individuals, only baroreflex gain is different, with the variability of phase being similar in both groups. These measurements of short-term circulatory control might help in risk stratification for sudden cardiac death.

A noninvasive measure of baroreflex sensitivity without blood pressure measurement.

BACKGROUND: Baroreflex sensitivity (BRS) and heart rate variability (HRV) are attenuated in cardiovascular disease and can give important prognostic information. Conventional measures of BRS require expensive or invasive equipment for the beat-to-beat measure of blood pressure (BP). We examined the possibility of developing a simple protocol that would provide a relatively standardized BP stimulus, which might obviate the need to measure BP beat-by-beat. METHODS AND RESULTS: Fifty-five patients with chronic heart failure (mean age 59 [SD 11] years) and 20 healthy control subjects (mean age 53 [SD 14] years, P not significant) underwent 5-minute recordings of BP (by photoplethysmograph) and R-R interval during 0.1-Hz controlled breathing. The size of the oscillations in BP was the same in the 2 groups (3.6 mm Hg vs 4.1 mm Hg, P =.5). There was, however, a significant difference in the amplitude of the R-R interval oscillations (77 ms vs 31 ms, P <.0001). The amplitude of the R-R interval oscillations correlated strongly with BRS (r = 0.81, P <.0001 with controlled breathing BRS, and r = 0.51, P <.0001 with alpha index). There was no correlation with the size of BP oscillations (r = -0.13, P not significant with controlled breathing BRS, and r = -0.15, P not significant with alpha index). In a separate study, a group of 22 young patients (mean age 36 years) with type I diabetes mellitus and 28 healthy control subjects (mean age 39 years) underwent measurement of resting HRV and amplitude of R-R interval oscillations during 0.1-Hz breathing. There was no significant difference in triangular index or low-frequency R-R interval power between the 2 groups. There was, however, a significant difference in the amplitude of R-R interval oscillations during controlled breathing between patients with diabetes and healthy control subjects. Total and high-frequency RR interval variability was also significantly different between the 2 groups. CONCLUSION: During 0.1-Hz breathing, the marked difference in BRS between patients with CHF and age-matched control subjects is the result of smaller R-R interval oscillations. In young patients with diabetes, these R-R interval oscillations are significantly smaller than age-matched control subjects, even when some measures of spontaneous HRV are not different between groups. Breathing at 0.1 Hz provides a standard BP stimulus and concentrates spectral power of heart rate at one frequency, enabling simple evaluation of BRS even when BP measurement is not available.

Abnormal temporal dynamics of blood pressure and RR interval regulation in patients with chronic heart failure: relationship to baroreflex sensitivity.

It is not known whether the temporal relationship between blood pressure (BP) and RR interval is modulated by the same mechanisms in normal controls and patients with chronic heart failure (CHF). We investigated this under conditions of controlled slow breathing. Fifty patients with CHF and 17 age-matched normals underwent recordings of BP and RR interval during 0.1 Hz controlled breathing. Fourier analysis was used to determine the phase relationships between the oscillations in respiration, BP and RR interval. There was no significant difference between patients and normals in the distribution of phase angle between respiration and BP (P=0.06) or between respiration and RR interval (P=0.21). There was, however, a significant difference in the phase relationship between BP and RR interval (P=0.03): in normals, BP led RR interval by a mean phase angle of 48.4 degrees (S.D. 16.8 degrees ). In patients with CHF, the distribution of phase difference was much wider [34.4 degrees (S.D. 62.8 degrees )]. The source of this wide distribution was patients with attenuated baroreflex sensitivity (BRS), with those with preserved BRS showing a relationship between BP and RR interval similar to the normal group. During controlled respiration, normal subjects exhibit a stereotyped relationship between oscillations in BP and RR interval, which is mediated by the baroreflex. This relationship is maintained in those patients with CHF who have a preserved BRS. In contrast, patients with an attenuated BRS show a wide distribution in the relationship between BP and RR interval ranging from completely in phase, to anti-phase. This may have important implications for the measurement and interpretation of BRS in patient groups where BRS is weak.

Predictors of new onset atrial fibrillation in patients with heart failure.

INTRODUCTION: Stroke associated with atrial fibrillation (AF) is more frequent in heart failure. It is unknown what variables predict future AF in these patients and how AF might evolve over time. We investigated this in patients with implantable cardiac defibrillators (ICD) where AF detection is optimal. METHODS: Single centre, retrospective, observational cohort study. All ischaemic cardiomyopathy patients with dual chamber, primary prevention ICD implants between Aug 2003 and Dec 2009 were screened and included if at implant, they had no known AF history. Nine variables were analysed. AF was defined as any atrial tachyarrhythmia ≥180 bpm and ≥30 s. Multivariable, binary logistic regression models were built by adding variables significant in the univariate models. Variables were retained in the final multivariate models if p<0.05. RESULTS: n=197 met the inclusion criteria (85.8% male, median age: 66.8 years). After median follow-up for 2.8 years, 44.2% developed AF. After univariate analysis, the baseline variables associated with AF after implant were age, NYHA class and renal impairment (RI, defined eGFR<60 ml/min/1.73 m2) (p<0.05). After multivariable analysis, the only variable which was associated with AF was RI (HR: 2.04 (CI: 1.10-3.79)). Two baseline variables were independently associated with all-cause mortality: RI (HR: 2.42 (1.14-5.12)) and non-white ethnicity. CONCLUSION: RI at time of implant was independently associated with both future AF and all-cause mortality during long-term follow-up. RI was a stronger predictor of AF than age. Those patients with heart failure and RI should be regularly screened for asymptomatic AF, regardless of age, to ensure that stroke prophylaxis may be initiated.

Diagnostic performance of hyperaemic myocardial blood flow index obtained by dynamic computed tomography: does it predict functionally significant coronary lesions?

AIMS: The severity of coronary artery narrowing is a poor predictor of functional significance, in particular in intermediate coronary lesions (30-70% diameter narrowing). The aim of this work was to compare the performance of a quantitative hyperaemic myocardial blood flow (MBF) index derived from adenosine dynamic computed tomography perfusion (CTP) imaging with that of visual CT coronary angiography (CTCA) and semi-automatic quantitative CT (QCT) in the detection of functionally significant coronary lesions in patients with stable chest pain. METHODS AND RESULTS: CTCA and CTP were performed in 80 patients (210 analysable coronary vessels) referred to invasive coronary angiography (ICA). The MBF index (mL/100 mL/min) was computed using a model-based parametric deconvolution method. The diagnostic performance of the MBF index in detecting functionally significant coronary lesions was compared with visual CTCA and QCT. Coronary lesions with invasive fractional flow reserve of ≤0.75 were defined as functionally significant. The optimal cut-off value of the MBF index to detect functionally significant coronary lesions was 78 mL/100 mL/min. On a vessel-territory level, the MBF index had a larger area under the curve (0.95; 95% confidence interval [95% CI]: 0.92-0.98) compared with visual CTCA (0.85; 95% CI: 0.79-0.91) and QCT (0.89; 95% CI: 0.84-0.93) (both P-values <0.001). In the analysis restricted to intermediate coronary lesions, the specificity of visual CTCA (69%) and QCT (77%) could be improved by the subsequent use of the MBF index (89%). CONCLUSION: In this proof-of-principle study, the MBF index performed better than visual CTCA and QCT in the identification of functionally significant coronary lesions. The MBF index had additional value beyond CTCA anatomy in intermediate coronary lesions. This may have a potential to support patient management.

Trauma-induced secondary cardiac injury is associated with hyperacute elevations in inflammatory cytokines.

INTRODUCTION: Clinical evidence supports the existence of a trauma-induced secondary cardiac injury. Experimental research suggests inflammation as a possible mechanism. The study aimed to determine if there was an early association between inflammation and secondary cardiac injury in trauma patients. METHODS: A cohort study of critically injured patients between January 2008 and January 2010 was undertaken. Levels of the cardiac biomarkers troponin I and heart-specific fatty acid-binding protein and the cytokines tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1ß, and IL-8 were measured on admission to hospital, and again at 24 and 72 h. Participants were reviewed for adverse cardiac events (ACEs) and in-hospital mortality. RESULTS: Of 135 patients recruited, 18 (13%) had an ACE. Patients with ACEs had higher admission plasma levels of TNF-α (5.4 vs. 3.8 pg/mL; P = 0.03), IL-6 (140 vs. 58.9 pg/mL, P = 0.009), and IL-8 (19.3 vs. 9.1 pg/mL, P = 0.03) compared with those without events. Hour 24 cytokines were not associated with events, but IL-8 (14.5 vs. 5.8 pg/mL; P = 0.01) and IL-1ß (0.55 vs. 0.19 pg/mL; P = 0.04) were higher in patients with ACEs at 72 hours. Admission IL-6 was independently associated with heart-specific fatty acid-binding protein increase (P < 0.05). Patients who presented with an elevated troponin I combined with either an elevated TNF-α (relative risk [RR], 11.0; 95% confidence interval [CI], 1.8-66.9; P = 0.015), elevated IL-6 (RR, 17.3; 95% CI, 2.9-101.4; P = 0.001), or elevated IL-8 (RR, 15.0; 95% CI, 3.1-72.9; P = 0.008) were at the highest risk of in-hospital death when compared with individuals with normal biomarker and cytokine values. CONCLUSIONS: There is an association between hyperacute elevations in inflammatory cytokines with cardiac injury and ACEs in critically injured patients. Biomarker evidence of cardiac injury and inflammation on admission is associated with a higher risk of in-hospital death.

Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis.

OBJECTIVES: This study sought to determine the effects of a p38 mitogen-activated protein kinase inhibitor, losmapimod, on vascular inflammation, by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography imaging. BACKGROUND: The p38 mitogen-activated protein kinase cascade plays an important role in the initiation and progression of inflammatory diseases, including atherosclerosis. METHODS: Patients with atherosclerosis on stable statin therapy (n = 99) were randomized to receive losmapimod 7.5 mg once daily (lower dose [LD]), twice daily (higher dose [HD]) or placebo for 84 days. Vascular inflammation was assessed by FDG positron emission tomography/computed tomography imaging of the carotid arteries and aorta; analyses focused on the index vessel (the artery with the highest average maximum tissue-to-background ratio [TBR] at baseline). Serum inflammatory biomarkers and FDG uptake in visceral and subcutaneous fat were also measured. RESULTS: The primary endpoint, change from baseline in average TBR across all segments in the index vessel, was not significantly different between HD and placebo (ΔTBR: -0.04 [95% confidence interval [CI]: -0.14 to +0.06], p = 0.452) or LD and placebo (ΔTBR: -0.02 [95% CI: -0.11 to +0.06], p = 0.579). However, there was a statistically significant reduction in average TBR in active segments (TBR ≥1.6) (HD vs. placebo: ΔTBR: -0.10 [95% CI: -0.19 to -0.02], p = 0.0125; LD vs. placebo: ΔTBR: -0.10 [95% CI: -0.18 to -0.02], p = 0.0194). The probability of a segment being active was also significantly reduced for HD when compared with placebo (OR: 0.57 [95% CI: 0.41 to 0.81], p = 0.002). Within the HD group, reductions were observed in placebo-corrected inflammatory biomarkers including high-sensitivity C-reactive protein (% reduction: -28% [95% CI: -46 to -5], p = 0.023) as well as FDG uptake in visceral fat (ΔSUV: -0.05 [95% CI: -0.09 to -0.01], p = 0.018), but not subcutaneous fat. CONCLUSIONS: Despite nonsignificant changes for the primary endpoint of average vessel TBR, HD losmapimod reduced vascular inflammation in the most inflamed regions, concurrent with a reduction in inflammatory biomarkers and FDG uptake in visceral fat. These results suggest a systemic anti-inflammatory effect. (A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging; NCT00633022).

Prediction model to estimate presence of coronary artery disease: retrospective pooled analysis of existing cohorts.

OBJECTIVES: To develop prediction models that better estimate the pretest probability of coronary artery disease in low prevalence populations. DESIGN: Retrospective pooled analysis of individual patient data. SETTING: 18 hospitals in Europe and the United States. PARTICIPANTS: Patients with stable chest pain without evidence for previous coronary artery disease, if they were referred for computed tomography (CT) based coronary angiography or catheter based coronary angiography (indicated as low and high prevalence settings, respectively). MAIN OUTCOME MEASURES: Obstructive coronary artery disease (≥ 50% diameter stenosis in at least one vessel found on catheter based coronary angiography). Multiple imputation accounted for missing predictors and outcomes, exploiting strong correlation between the two angiography procedures. Predictive models included a basic model (age, sex, symptoms, and setting), clinical model (basic model factors and diabetes, hypertension, dyslipidaemia, and smoking), and extended model (clinical model factors and use of the CT based coronary calcium score). We assessed discrimination (c statistic), calibration, and continuous net reclassification improvement by cross validation for the four largest low prevalence datasets separately and the smaller remaining low prevalence datasets combined. RESULTS: We included 5677 patients (3283 men, 2394 women), of whom 1634 had obstructive coronary artery disease found on catheter based coronary angiography. All potential predictors were significantly associated with the presence of disease in univariable and multivariable analyses. The clinical model improved the prediction, compared with the basic model (cross validated c statistic improvement from 0.77 to 0.79, net reclassification improvement 35%); the coronary calcium score in the extended model was a major predictor (0.79 to 0.88, 102%). Calibration for low prevalence datasets was satisfactory. CONCLUSIONS: Updated prediction models including age, sex, symptoms, and cardiovascular risk factors allow for accurate estimation of the pretest probability of coronary artery disease in low prevalence populations. Addition of coronary calcium scores to the prediction models improves the estimates.