Tania Pawade

Valvular (18)F-Fluoride and (18)F-Fluorodeoxyglucose Uptake Predict Disease Progression and Clinical Outcome in Patients With Aortic Stenosis.

18F-Fluoride is a positron emission tomography (PET) radiotracer that preferentially binds to regions of newly forming vascular microcalcifications beyond the resolution of computed tomography (CT) [(1)][1]. 18F-Fluorodeoxyglucose (18F-FDG) has been widely used to measure vascular inflammation [(2

RISK STRATIFICATION IN PATIENTS WITH AORTIC STENOSIS USING NOVEL IMAGING APPROACHES

The prevalence of calcific aortic stenosis increases with age, occurring in 3% to 5% of individuals aged >75 years.1,2 The narrowing of the aortic valve is driven by a highly complex and intricately regulated process of inflammation, fibrosis, and calcification, which eventually results in leaflet immobility and the associated hemodynamic consequences.3 In response to the narrowed valve, left ventricular hypertrophy is initially adaptive to restore wall stress and cardiac performance. Ultimately, adverse events, such as symptoms, heart failure, and death, occur as the left ventricle decompensates. This transition from adaptation to decompensation is driven by progressive myocyte death and myocardial fibrosis.4–6 Therefore, it is important to consider aortic stenosis as a condition that affects both the valve and the myocardium.5,6 Indeed, contemporary guidelines recommend aortic valve replacement in patients with severe aortic stenosis and evidence of advanced ventricular decompensation, defined by either the presence of symptoms or an impaired systolic ejection fraction <50%.7,8 The current strategy relies heavily on the timely identification of symptoms. However, the poor prognosis associated with the development of angina, exertional dyspnea, and syncope first described by Ross and Braunwald4 in 1968 was based on younger patients with bicuspid or rheumatic disease (average age of 63 years at the time of death). Establishing symptoms in the more elderly population encountered in current clinical practice is more challenging because of their comorbidities and often sedentary lifestyles. Moreover, it is now widely recognized that left ventricular ejection fraction is not a sensitive marker of myocardial dysfunction,9,10 and impairment in ejection fraction is often a late manifestation that may not be reversible.11,12 Furthermore, there is an urgent need to improve our understanding of the pathogenesis of aortic stenosis, both …

Cardiac αVβ3 integrin expression following acute myocardial infarction in humans

Objective Maladaptive repair contributes towards the development of heart failure following myocardial infarction (MI). The αvβ3 integrin receptor is a key mediator and determinant of cardiac repair. We aimed to establish whether αvβ3 integrin expression determines myocardial recovery following MI. Methods 18F-Fluciclatide (a novel αvβ3-selective radiotracer) positron emission tomography (PET) and CT imaging and gadolinium-enhanced MRI (CMR) were performed in 21 patients 2 weeks after ST-segment elevation MI (anterior, n=16; lateral, n=4; inferior, n=1). CMR was repeated 9 months after MI. 7 stable patients with chronic total occlusion (CTO) of a major coronary vessel and nine healthy volunteers underwent a single PET/CT and CMR. Results 18F-Fluciclatide uptake was increased at sites of acute infarction compared with remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17; p<0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p<0.001). There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with activity similar to the myocardium of healthy volunteers (TBRmean 0.71±0.06 vs 0.70±0.03, p=0.83). 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p<0.001) and subendocardial infarction. Importantly, although there was no correlation with infarct size (r=0.03, p=0.90) or inflammation (C reactive protein, r=−0.20, p=0.38), 18F-fluciclatide uptake was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery. Conclusion 18F-Fluciclatide uptake is increased at sites of recent MI acting as a biomarker of cardiac repair and predicting regions of recovery. Trial registration number NCT01813045; Post-results.

Optimization and Reproducibility of Aortic Valve 18F-Fluoride Positron Emission Tomography in Patients With Aortic Stenosis

Background—18F-Fluoride positron emission tomography (PET) and computed tomography (CT) can measure disease activity and progression in aortic stenosis. Our objectives were to optimize the methodology, analysis, and scan–rescan reproducibility of aortic valve 18F-fluoride PET-CT imaging. Methods and Results—Fifteen patients with aortic stenosis underwent repeated 18F-fluoride PET-CT. We compared nongated PET and noncontrast CT, with a modified approach that incorporated contrast CT and ECG-gated PET. We explored a range of image analysis techniques, including estimation of blood-pool activity at differing vascular sites and a most diseased segment approach. Contrast-enhanced ECG-gated PET-CT permitted localization of 18F-fluoride uptake to individual valve leaflets. Uptake was most commonly observed at sites of maximal mechanical stress: the leaflet tips and the commissures. Scan–rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in percentage error from ±63% to ±10% (tissue to background ratio MDS mean of 1.55, bias −0.05, limits of agreement −0·20 to +0·11). Conclusions—Optimized 18F-fluoride PET-CT allows reproducible localization of calcification activity to different regions of the aortic valve leaflet and commonly to areas of increased mechanical stress. This technique holds major promise in improving our understanding of the pathophysiology of aortic stenosis and as a biomarker end point in clinical trials of novel therapies. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02132026.

Diagnostic and prognostic benefits of computed tomography coronary angiography using the 2016 National Institute for Health and Care Excellence guidance within a randomised trial

Objectives To evaluate the diagnostic and prognostic benefits of CT coronary angiography (CTCA) using the 2016 National Institute for Health and Care Excellence (NICE) guidelines for the assessment of suspected stable angina. Methods Post hoc analysis of the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial of 4146 participants with suspected angina randomised to CTCA. Patients were dichotomised into NICE guideline-defined possible angina and non-anginal presentations. Primary (diagnostic) endpoint was diagnostic certainty of angina at 6 weeks and prognostic endpoint comprised fatal and non-fatal myocardial infarction (MI). Results In 3770 eligible participants, CTCA increased diagnostic certainty more in those with possible angina (relative risk (RR) 2.22 (95% CI 1.91 to 2.60), p<0.001) than those with non-anginal symptoms (RR 1.30 (1.11 to 1.53), p=0.002; pinteraction <0.001). In the possible angina cohort, CTCA did not change rates of invasive angiography (p=0.481) but markedly reduced rates of normal coronary angiography (HR 0.32 (0.19 to 0.52), p<0.001). In the non-anginal cohort, rates of invasive angiography increased (HR 1.82 (1.13 to 2.92), p=0.014) without reducing rates of normal coronary angiography (HR 0.78 (0.30 to 2.05), p=0.622). At 3.2 years of follow-up, fatal or non-fatal MI was reduced in patients with possible angina (3.2% to 1.9%%; HR 0.58 (0.34 to 0.99), p=0.045) but not in those with non-anginal symptoms (HR 0.65 (0.25 to 1.69), p=0.379). Conclusions NICE-guided patient selection maximises the benefits of CTCA on diagnostic certainty, use of invasive coronary angiography and reductions in fatal and non-fatal myocardial infarction. Patients with non-anginal chest pain derive minimal benefit from CTCA and increase the rates of invasive investigation. Trial registration number ClinicalTrials.gov: NCT01149590;post results.

Cardiovascular Effects of Urocortin 2 and Urocortin 3 in Patients with Chronic Heart Failure

Aims Urocortin 2 and urocortin 3 may play a role in the pathophysiology of heart failure and are emerging therapeutic targets. We aimed to examine the local and systemic cardiovascular effects of urocortin 2 and urocortin 3 in healthy subjects and patients with heart failure. Methods Patients with heart failure (n = 8) and age and gender‐matched healthy subjects (n = 8) underwent bilateral forearm arterial blood flow measurement using forearm venous occlusion plethysmography during intra‐arterial infusions of urocortin 2 (3.6–36 pmol min−1), urocortin 3 (360–3600 pmol min−1) and substance P (2–8 pmol min−1). Heart failure patients (n = 9) and healthy subjects (n = 7) underwent non‐invasive impedance cardiography during incremental intravenous infusions of sodium nitroprusside (573–5730 pmol kg−1 min−1 ), urocortin 2 (36–360 pmol min−1 ), urocortin 3 (1.2–12 nmol min−1) and saline placebo. Results Urocortin 2, urocortin 3 and substance P induced dose‐dependent forearm arterial vasodilatation in both groups (P < 0.05 for both) with no difference in magnitude of vasodilatation between patients and healthy subjects. During systemic intravenous infusions, urocortin 3 increased heart rate and cardiac index and reduced mean arterial pressure and peripheral vascular resistance index in both groups (P < 0.01 for all). Urocortin 2 produced similar responses to urocortin 3, although increases in cardiac index and heart rate were only significant in heart failure (P < 0.05) and healthy subjects (P < 0.001), respectively. Conclusion Urocortins 2 and 3 cause vasodilatation, reduce peripheral vascular resistance and increase cardiac output in both health and disease. These data provide further evidence to suggest that urocortins 2 and 3 continue to hold promise for the treatment of heart failure.

Aortic stenosis begets aortic stenosis: between a rock and a hard place?

Aortic stenosis is the major cause of valve disease in the Western world and a growing healthcare burden. We lack medication capable of slowing disease progression and so rely on aortic valve replacement in patients with severe disease and symptoms. Predicting when this will occur is challenging with the literature suggesting on average slow progression with wide individual variation (rate of change in the mean gradient of ∼3±3 mm Hg/year). Annual or biannual clinical review is therefore required in all patients with serial echocardiography performed in order to track progressive valve narrowing.1 This incurs significant costs and a method capable of predicting the future natural history of aortic stenosis and the likely timing of valve surgery could help streamline patient care. It is on this background that Nguyen et al 2 investigated whether an association exists between baseline aortic stenosis severity and the rate of disease progression. In 149 patients with largely mild and moderate disease, the average rate of haemodynamic progression after a mean follow-up of 2.9±1.0 years was again +3±3 mm Hg/year (mean gradient). As anticipated the fastest rates of progression were observed in those patients with the most advanced aortic stenosis …

Motion-corrected imaging of the aortic valve with (18)F-NaF PET/CT and PET/MR: a feasibility study

We investigated whether motion correction of gated 18F-fluoride PET/CT and PET/MRI of the aortic valve could improve PET quantitation and image quality. Methods: A diffeomorphic, mass-preserving, anatomy-guided registration algorithm was used to align the PET images from 4 cardiac gates, preserving all counts, and apply them to the PET/MRI and PET/CT data of 6 patients with aortic stenosis. Measured signal-to-noise ratios (SNRs) and target-to-background ratios (TBRs) were compared with the standard method of using only the diastolic gate. Results: High-intensity aortic valve 18F-fluoride uptake was observed in all patients. After motion correction, SNR and TBR increased compared with the median diastolic gate (SNR, 51.61 vs. 21.0; TBR, 2.85 vs. 2.22) and the median summed data (SNR, 51.61 vs. 34.10; TBR, 2.85 vs. 1.95) (P = 0.028 for all). Furthermore, noise decreased from 0.105 (median, diastolic) to 0.042 (median, motion-corrected) (P = 0.028). Conclusion: Motion correction of hybrid 18F-fluoride PET markedly improves SNR, resulting in improved image quality.

High-Sensitivity Cardiac Troponin I and the Diagnosis of Coronary Artery Disease in Patients With Suspected Angina Pectoris

Background: We determined whether high-sensitivity cardiac troponin I can improve the estimation of the pretest probability for obstructive coronary artery disease (CAD) in patients with suspected stable angina. Methods and Results: In a prespecified substudy of the SCOT-HEART trial (Scottish Computed Tomography of the Heart), plasma cardiac troponin was measured using a high-sensitivity single-molecule counting assay in 943 adults with suspected stable angina who had undergone coronary computed tomographic angiography. Rates of obstructive CAD were compared with the pretest probability determined by the CAD Consortium risk model with and without cardiac troponin concentrations. External validation was undertaken in an independent study population from Denmark comprising 487 patients with suspected stable angina. Higher cardiac troponin concentrations were associated with obstructive CAD with a 5-fold increase across quintiles (9%–48%; P<0.001) independent of known cardiovascular risk factors (odds ratio, 1.35; 95% confidence interval, 1.25–1.46 per doubling of troponin). Cardiac troponin concentrations improved the discrimination and calibration of the CAD Consortium model for identifying obstructive CAD (C statistic, 0.788–0.800; P=0.004; &khgr;2=16.8 [P=0.032] to 14.3 [P=0.074]). The updated model also improved classification of the American College of Cardiology/American Heart Association pretest probability risk categories (net reclassification improvement, 0.062; 95% confidence interval, 0.035–0.089). The revised model achieved similar improvements in discrimination and calibration when applied in the external validation cohort. Conclusions: High-sensitivity cardiac troponin I concentration is an independent predictor of obstructive CAD in patients with suspected stable angina. Use of this test may improve the selection of patients for further investigation and treatment. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01149590.

Noninvasive imaging for the diagnosis and prognosis of pulmonary hypertension

Pulmonary hypertension (PH) is a major cause of morbidity and mortality, but it often presents with nonspecific symptoms, thereby delaying diagnosis and treatment. While invasive cardiac catheterization is essential to confirm the diagnosis, patients with breathlessness are commonly encountered in clinical practice creating a demand for noninvasive screening methods. Preliminary investigations such as the electrocardiogram and chest radiograph lack sensitivity even in advanced cases. Echocardiography is used to screen patients; however, over-reliance on a single estimation of pulmonary artery systolic pressure is unwise, instead multiple parameters should be assessed. Once a diagnosis of PH is made, radionuclide imaging should be performed to exclude chronic thromboembolic disease, and computed tomography is vital for eliminating parenchymal lung disease as a potential etiology. Currently, the primary contribution of cardiac MRI is the accurate assessment of right ventricular size and function. In this respect, cardiac MRI may be supportive during diagnosis of PH, but the main importance of this is in defining prognosis although new outcome variables are anticipated.