485 research outputs found
Cardiovascular magnetic resonance and positron emission tomography in the assessment of aortic stenosis
No full textBackground
Aortic stenosis is not only characterized by progressive valve narrowing but also by
the hypertrophic response of the left ventricle that ensues. In this most common
valvular condition novel imaging approaches (cardiovascular magnetic resonance
[CMR] and positron emission tomography [PET]) have shown promise in the
assessment of disease progression and risk stratification. The central aim of this
thesis was to investigate the potential of CMR imaging to refine risk prediction and to
improve the imaging protocol of 18F-sodium fluoride PET for aortic stenosis.
Methods and Results
Asymmetric wall thickening in aortic stenosis
In a prospective observational cohort study, 166 patients with aortic stenosis (age 69,
69% males, mean aortic valve area 1.0±0.4cm2) and 37 age and sex-matched
healthy volunteers underwent phenotypic characterisation with comprehensive
clinical, imaging and biomarker evaluation. Asymmetric wall thickening on both
echocardiography and cardiovascular magnetic resonance was defined as regional
wall thickening ≥13 mm and >1.5-fold the thickness of the opposing myocardial
segment.
Asymmetric wall thickening was observed in 26% (n=43) of patients with aortic
stenosis using magnetic resonance and 17% (n=29) using echocardiography. Despite
similar demographics, co-morbidities, valve narrowing, myocardial hypertrophy and
fibrosis, patients with asymmetric wall thickening had increased cardiac troponin I and
brain natriuretic peptide concentrations (both p<0.001). Over 28 [22, 33] months of
follow-up, asymmetric wall thickening was an independent predictor of aortic valve
replacement or death whether detected by magnetic resonance (HR=2.15; 95 CI 1.29
to 3.59; p=0.003) or echocardiography (HR=1.79; 95 CI 1.08 to 3.69; p=0.021).
Animal model of pressure overload
We performed serial Cardiac Magnetic Resonance (CMR) imaging every 2-week in
31 mice subjected to pressure overload (continuous angiotensin II infusion) for 6
weeks and investigated reverse remodelling by repeating CMR 1 month following
normalization of afterload (n=9). Cine CMR was used to measure left ventricular
volumes, mass, and systolic function whilst myocardial fibrosis was assessed using
indexed ECV (iECV) calculated from T1-relaxation times acquired with a small animal
modified look-locker inversion recovery sequence.
During the initial phase of increased pressure afterload indices of left ventricular
hypertrophy (0.091 [0.083, 0.105] vs 0.123 [0.111, 0.138] g) and myocardial fibrosis
(iECV: 0.022 [0.019, 0.024] vs 0.022 [0.019, 0.024] mL) increased in line with blood
pressure measurements (65.1±12.0 vs 84.7±9.2 mmHg) whilst left ventricular ejection
fraction (LVEF, 59.3 [57.6, 59.9] vs 46.9 [38.5, 49.6] %) deteriorated significantly (all
p≤0.01 compared to baseline).
During the reverse remodelling phase blood pressure normalized (68.8±5.4 vs
65.1±12.0 mmHg, p=0.42 compared to baseline). Whilst LV mass (0.108 [0.098,
0.116] vs 0.091 [0.083, 0.105] g) and iECV (0.034 [0.032, 0.036] vs 0.022 [0.019,
0.024] mL) improved both remained elevated compared to baseline (p<0.05).
Similarly, the LVEF remained impaired 51.1 [42.9, 52.8] vs 59.3 [57.6, 59.9] %,
p=0.03. There was a strong association between LVEF and iECV values during
pressure overload (r=-0.88, p<0.001).
Gender differences in aortic stenosis
Two hundred forty-nine patients (66±13 years, 30% women) with at least mild AS
were recruited from two prospective observational cohort studies and underwent
comprehensive Doppler echocardiography and CMR exams. On CMR, T1 mapping
was used to quantify extracellular volume (ECV) fraction as a marker of diffuse
fibrosis, and late gadolinium enhancement (LGE) was used to assess focal fibrosis.
There was no difference in age between women and men (66±15 vs 66±12 years,
p=0.78). However, women presented a better cardiovascular risk profile than men
with less hypertension, dyslipidemia, diabetes, and coronary artery disease (all
p≤0.10). As expected, LV mass index measured by CMR was smaller in women than
in men (p<0.0001). Despite fewer comorbidities, women presented larger ECV
fraction [29.0 (27.4-30.6) vs. 26.8 (25.1-28.7) %, p<0.0001] and similar LGE [4.5 (2.3-
7.0) vs. 2.8 (0.6-6.8) %, p=0.20] than men. In multivariable analysis, female sex
remained an independent determinant of higher ECV fraction and LGE (both p≤0.05).
Prior CT angiography for PET
Forty-five patients (age 67.1±6.9 years, 76% males) underwent CTA (CTA1) and
combined 18F-NaF PET/CTA (CTA2) imaging within 14 [10,21] days. We fused CTA1
from visit one with 18F-NaF PET from the second visit (PET) and compared visual
pattern of activity, maximal standard uptake values (SUVmax) and target to
background (TBR) measurements on (PET/CTA1) fused versus hybrid (PET/CTA2)
data.
On PET/CTA2, 226 coronary plaques were identified. Fifty-eight coronary segments
from 28 (62%) patients had high 18F-NaF uptake (TBR>1.25), whilst 168 segments
had lesions with 18F-NaF TBR ≤1.25. Uptake in all lesions was categorized identically
on co-registered PET/CTA1. There was no significant difference in 18F-NaF uptake
values between PET/CTA1 and PET/CTA2 (SUVmax: 1.16±0.40 vs. 1.15±0.39,
p=0.53; TBR:1.10±0.45 vs. 1.09±0.46, p=0.55). The intraclass correlation coefficient
for SUVmax and TBR was 0.987 (95%CI 0.983 to 0.991) and 0.986 (95%CI 0.981 to
0.992). There was no fixed or proportional bias between PET/CTA1 and PET/CTA2
for SUVmax and TBR. Cardiac motion correction of PET scans improved
reproducibility with tighter 95% limits of agreement (±0.14 for SUVmax and ±0.15 for
TBR vs. ±0.20 and ±0.20 on diastolic imaging; p<0.001).
Delayed PET imaging
Twenty patients (67±7years old, 55% male) with stable coronary artery disease
underwent coronary CT angiography and PET/CT both 1 h and 3 h after the injection
of 266.2±13.3 MBq of 18F-NaF. We compared the visual pattern of coronary uptake,
maximal background (blood pool) activity, noise, standard uptake values (SUVmax),
corrected SUV (cSUVmax) and target to background (TBR) measurements in lesions
defined by CTA on 1h vs 3h post injection 18F-NaF PET.
On 1h PET 26 CTA lesions with 18F-NaF PET uptake were identified in 12 (60%)
patients. On 3h PET we detected 18F-NaF PET uptake in 7 lesions which were not
identified on the 1h PET. The median cSUVmax and TBR values of these lesions
were 0.48 [interquartile range (IQR) 0.44-0.51] and 1.45 [IQR, 1.39-1.52] compared
to -0.01 [IQR, -0.03-0.001] and 0.95 [IQR, 0.90-0.98] on 1h PET, both p<0.001.
Across the entire cohort 3h PET SUVmax values were similar to 1h PET
measurements 1.63 [IQR, 1.37-1.98] vs. 1.55 [IQR, 1.43-1.89], p=0.30 and the
background activity was lower 0.71 [IQR, 0.65-0.81] vs. 1.24 [IQR, 1.05-1.31],
p<0.001. On 3h PET, the TBR values, cSUVmax and the noise were significantly
higher (2.30 [IQR, 1.70-2.68] vs 1.28 [IQR, 0.98-1.56], p<0.001; 0.38 [IQR, 0.27-0.70]
vs 0.90 [IQR, 0.64-1.17], p<0.001 and 0.10 [IQR, 0.09-0.12] vs. 0.07 [IQR, 0.06-0.09],
p=0.02). The median cSUVmax and TBR values increased by 92% (range: 33-225%)
and 80% (range: 20-177%).
Conclusions
In aortic stenosis, asymmetric wall thickening is associated with adverse prognosis,
in this condition there are significant differences in the fibrosis burden between male
and female patients and the adverse remodeling of the ventricle can be reproduced
in a simple animal model of pressure overload. For 18F-NaF PET utilizing a CT
angiography acquired before the PET acquisition enables adequate uptake
quantification and delayed emission scanning facilitates image analysis
Late gadolinium enhancement as a potential marker of increased perioperative risk in aortic valve replacement
No full textOBJECTIVES: Risk assessment of patients with aortic stenosis (AS) undergoing aortic valve replacement (AVR) is challenging. We set out to determine the impact of myocardial late gadolinium enhancement (LGE), as detected by cardiovascular magnetic resonance (CMR), on postoperative outcomes following AVR.METHODS: A prospective observational study was conducted on patients undergoing CMR using the LGE technique within 1 year of subsequent AVR. Patients were categorized into absent, mid-wall or infarct patterns of LGE by independent observers blinded to all clinical data, and data were collected with regard to 30-day mortality, major adverse cardiac and cerebrovascular events (MACCE) and postoperative complications.RESULTS: A total of 63 patients were studied. Twenty-five patients had no LGE; 20 had mid-wall LGE and 18 had an infarct pattern. The incidence of MACCE, cerebrovascular accident (CVA) and heart block were significantly higher in the mid-wall group compared with the other two groups (MACCE: 25 vs. 0 vs. 5%, P = 0.014; CVA: 20 vs. 0 vs. 0%, P = 0.013; heart block: 30 vs. 4 vs. 12%, P = 0.050). Patients with no LGE had no 30-day MACCE events and no deaths up to 2 years of follow-up.CONCLUSIONS: The myocardial LGE holds promise as a means of predicting risk prior to AVR for AS
Valve and the ventricle: advances in the assessment and management of aortic stenosis
No full textBackground
Aortic stenosis is the commonest valve disease in the Western world, progresses inexorably
over years and has no effective lifestyle or drug treatments. Left untreated, aortic stenosis
leads to symptoms such as breathlessness and chest pain, followed by cardiac failure and
death. Aortic valve replacement (AVR) is the only treatment, for which surgery has been the
default technique for decades. Transcatheter aortic valve implantation (TAVI), a much less
invasive strategy, has substantially expanded the population in whom we now consider AVR.
Importantly, the implantation of a prosthetic valve should be considered a means of
converting a patient with severe native valve disease to a patient with a well-functioning
prosthesis, rather than a cure for valve disease per se. There are potential complications that
can arise following successful valve replacement, including valve thrombosis and structural
valve degeneration.
Given the above, several controversies and questions exist. These include: 1) What is the
optimal method of assessing aortic stenosis severity in low-flow states and in valves where
fibrosis contributes significantly to valve obstruction? 2) Are there deleterious effects on
myocardial health from aortic stenosis that occur prior to symptom onset or a fall in ejection
fraction, and that provide prognostic information? 3) Are there drug therapies that can retard
the progression of aortic stenosis? 4) Are there novel methods of detecting bioprosthetic
valve thrombus that may provide insight into mechanisms governing valve durability?
Methods
In study one, we developed a unique method of assessing the anatomy of the aortic valve and
the severity of aortic stenosis using contrast-enhanced computed tomography (CT). This
method has several advantages over non-contrast CT aortic valve calcium scoring (CT-AVC)
– the current standard flow-independent measure of aortic stenosis severity – which include
spatial resolution, anatomical definition and the ability to quantify non-calcific leaflet
thickening in addition to calcific volume. This technique was applied in a post-hoc analysis
of a prospectively recruited population of patients with aortic stenosis enrolled in a
randomised controlled trial. Patients had undergone standardised echocardiography, non-contrast CT and contrast-enhanced CT.
In study two, we investigated a novel echocardiographic measurement, first-phase ejection
fraction (EF1), in aortic stenosis. This parameter is the ejection fraction measured at the time
of peak aortic velocity, rather than across the entire cardiac cycle, and is a measure of early
left ventricular contractility which can be impaired in aortic stenosis. This technique was
applied in a post-hoc analysis of a prospectively recruited population of patients with aortic
stenosis enrolled in an observational study. Patients had undergone standardised
echocardiography and cardiac magnetic resonance (CMR). Subsequent AVR and death were
captured from medical records.
In study three, we undertook a double-blind randomised controlled clinical trial of the anti-osteoporotic drugs denosumab and alendronic acid to determine whether they could slow
disease progression in aortic stenosis. This hypothesis arose from a body of pre-clinical and
observational data suggesting that bone turnover and osteoblastic differentiation of valvular
interstitial cells are important contributory mechanisms to aortic valve calcification, and that
modification of the receptor activator of nuclear kappa B (RANK)
ligand/RANK/osteoprotegerin axis might ameliorate valvular calcification. Patients were
randomised in a 2:1:2:1 ratio to denosumab (60 mg every 6 months), placebo injection,
alendronic acid (70 mg once weekly) or placebo capsule. Participants underwent serial
assessments with Doppler echocardiography, CT-AVC and 18F-sodium fluoride (18F-NaF)
positron emission tomography and computed tomography (PET-CT). The primary endpoint
was the calculated 24-month change in CT-AVC.
In study four, we undertook the first ever cardiac study of 18F-GP1. This is a novel
radiotracer that binds to the glycoprotein IIb/IIIa receptor, which are upregulated on activated
platelets. We investigated whether 18F-GP1 PET-CT could detect thrombus formation on
bioprosthetic aortic valves. First, ex vivo validation of 18F-GP1 binding was conducted in
explanted bioprosthetic valves leaflets using histology (Movat’s pentachrome),
immunohistochemistry (CD41) and autoradiography (18F-GP1). Second, patients with
bioprosthetic aortic valve prostheses who were not on anticoagulation were enrolled and
underwent standardised echocardiography and 18F-GP1 PET-CT. Patients with normal
native aortic valves who had undergone 18F-GP1 PET-CT as part of a contemporaneous
study formed a control cohort. Two patients with clinically confirmed obstructive
bioprosthetic valve thrombosis, recruited as part of a proof-of-concept case series by
collaborators in Germany, were also included in the analysis.
Results
In study one, 164 patients with aortic stenosis were included for analysis (78% male; 41 mild,
89 moderate, 34 severe). We demonstrated that non-calcific and calcific aortic valve leaflet
volumes on contrast-enhanced CT correlated well with echocardiographic peak aortic jet
velocity (r=0.67, p<0.001). In particular, quantification of the total non-calcific and calcific
leaflet volume demonstrated better correlation with echocardiographic peak aortic velocity
than non-contrast CT-AVC in women (r=0.72 and r=0.38 respectively).
In study two, 149 patients with aortic stenosis were included for analysis (70% male; 34 mild,
40 moderate, 75 severe). We demonstrated that EF1 can be impaired despite a normal overall
ejection fraction, that a low EF1 is associated with increased global left ventricular afterload
and more myocardial fibrosis, and that there is a potential for EF1 to improve following
AVR. Importantly, a low EF1 was associated with future AVR or death, independent of mean
aortic valve gradient (hazard ratio 5.6, 95% confidence interval 3.4-9.1).
In study three, we enrolled and randomised 150 patients (mean age 72±8 years, 21% female,
peak aortic jet velocity 3.36 [interquartile range 2.93 to 3.82] m/s) to denosumab (n=49),
alendronic acid (n=51) or placebo tablet or injection (total n=50). Despite an unequivocal
pharmacodynamic effect of the active drugs, as confirmed by a halving of the serum C-terminal telopeptide concentration at 6 months in the denosumab and alendronic acid arms,
we found no differences in 24-month change in CT-AVC between denosumab and placebo
(343 [198 to 804] Agatston Units (AU) versus 354 [76 to 675] AU, p=0.41), or alendronic
acid and placebo (326 [138 to 813] AU versus 354 [76 to 675] AU, p=0.49). Similarly, there
were no differences in change in peak aortic jet velocity or 18F-NaF aortic valve uptake.
In study four, we undertook 18F-GP1 PET-CT in 75 participants (53 with bioprosthetic
valves, median time from implantation 37 [12 to 80] months; 22 with normal native valves).
All bioprosthetic valves, but no native aortic valves, demonstrated focal 18F-GP1 uptake in
the valve leaflets. On multivariable analysis, higher 18F-GP1 uptake was independently
associated with duration of valve implantation (p=0.002) and hypoattenuated leaflet
thickening (p=0.004) but not with valve type. One patient had suspected clinical valve
thrombosis, confirmed on 18F-GP1 PET-CT, in addition to the two patients with known
obstructive valve thrombosis. All 3 were anticoagulated for 3 months, leading to resolution of
symptoms, improvement in mean valve gradients and a reduction in 18F-GP1 uptake. Extra-valvular 18F-GP1 uptake was evident across a range of extra-valvular prosthetic material
such as aortic interposition grafts and pacemaker leads.
Conclusions
We have demonstrated that contrast-enhanced CT assessments of non-calcific and calcific
aortic valve leaflet volumes correlated well with echocardiographic assessments of aortic
stenosis severity. This technique has clear benefits over non-contrast CT-AVC. We envisage
the potential for standard integration of contrast-enhanced leaflet volume assessments into
routine TAVI workflows, where a large proportion of patients have discordant
echocardiographic findings, and in patients where the contribution of fibrosis, rather than
purely calcium, may lead to underestimation of stenosis severity as assessed by CT-AVC. We
went on to show that EF1 is a potentially useful echocardiographic measure of early left
ventricular systolic dysfunction that may help risk stratification in patients with
asymptomatic severe aortic stenosis. This is pertinent in the current era where early AVR is
being tested in several randomised controlled trials. Additionally, we conclusively
demonstrate in a randomised controlled trial that neither denosumab nor alendronic acid
substantially affect the progression of aortic stenosis. This was a disappointing result but an
important finding that also highlights the importance of randomised controlled trials when
investigating causal relationships. Finally, 18F-GP1 PET-CT may have utility in identifying
focal areas of thrombus and distinguishing them from other causes of hypoattenuation on CT
as well as providing a novel approach to explore factors that may influence valve
thrombogenicity and durability. Taken together, these four studies have provided incremental
advances in the diagnosis, assessment and follow-up of patients with aortic stenosis as well as
generated major impetus for future clinical studies in this important and topical field
COVID-19 pandemic and cardiac imaging: EACVI recommendations on precautions, indications, prioritization, and protection for patients and healthcare personnel
No full textThis is a pre-copyedited, author-produced version of an article accepted for publication in Cardiovascular Research following peer review. The version of record Helge Skulstad, Bernard Cosyns, Bogdan A Popescu, Maurizio Galderisi, Giovanni Di Salvo, Erwan Donal, Steffen Petersen, Alessia Gimelli, Kristina H Haugaa, Denisa Muraru, Ana G Almeida, Jeanette Schulz-Menger, Marc R Dweck, Gianluca Pontone, Leyla Elif Sade, Bernhard Gerber, Pal Maurovich-Horvat, Tara Bharucha, Matteo Cameli, Julien Magne, Mark Westwood, Gerald Maurer, Thor Edvardsen, COVID-19 pandemic and cardiac imaging: EACVI recommendations on precautions, indications, prioritization, and protection for patients and healthcare personnel, European Heart Journal - Cardiovascular Imaging, , jeaa072, https://doi.org/10.1093/ehjci/jeaa072 is available online at: https://doi.org/10.1093/ehjci/jeaa072
Imaging microcalcium in thoracic aortic disease
No full textBACKGROUND:
Disease of the thoracic aorta occurs in two major forms; atheroma and aneurysm formation. Both disease processes progress silently before catastrophic complications occur, such as stroke or aortic dissection. Current management strategies focus on preventative interventions which can include high-risk surgery. However, identifying those who are most appropriate for such interventions is challenging. Deposition of calcium crystals (microcalcification) in the aortic wall occurs as a response to inflammation, cell stress and death, and its presence is thought to confer a vulnerable disease state in both thoracic aortic atheroma and aneurysm formation. 18F-Sodium fluoride positron emission tomography (PET) identifies microcalcification not identifiable on conventionally computed tomography (CT). The aim of this thesis was to assess the application of 18F-sodium fluoride PET in identifying of patients with high-risk thoracic aortic disease.
METHODS AND RESULTS:
Reproducibility:
The intra- and inter-rater repeatability as well as scan-rescan reproducibility of thoracic aortic 18F-sodium fluoride activity was measured for standard slice-by-slice methods, as well as a novel centreline-based method, in 20 patients undergoing two 18F-sodium fluoride PET-CT scans, no more than three weeks apart. We found that the novel centreline-based method was over 5 times quicker than standard methods (3.4±0.5 versus 15.1±1.7 min, P>0.0001), and had excellent intra- (intraclass correlation coefficient 0.98), and inter-rater repeatability (intraclass correlation coefficient 0.97). Scan-rescan reproducibility was very good (intraclass correlation coefficient 0.86) with a minimal mean error of 0.00, narrow 95% limits of agreement of - 0.13 to 0.13, and a coefficient of reproducibility of 0.11.
Microcalcification, aortic atheroma and stroke:
Arterial 18F-sodium fluoride PET identifies an early and active stage of atheromatous disease that is associated with plaque vulnerability and the culprit lesions underlying atherothrombotic events. In a post-hoc observational cohort study, thoracic aortic 18F-sodium fluoride activity was quantified in 461 patients with stable cardiovascular disease undergoing PET-CT. Progression of atherosclerosis was assessed by change in aortic and coronary CT calcium volume. Clinical outcomes were determined by the occurrence of ischaemic stroke. After 12.7±2.7 months, progression of thoracic aortic calcium volume correlated with baseline thoracic aortic 18F-sodium fluoride activity (n=140, r=0.31, p=0.00016). In 461 patients, 23 (5%) patients experienced an ischemic stroke after 6.1±2.3 years of follow up. High thoracic aortic 18F-sodium fluoride activity was strongly associated with ischaemic stroke (HR 10.3 [3.1 to 34.8], p=0.0017). In a multivariable Cox regression model including imaging and clinical risk factors, thoracic aortic 18F-sodium fluoride activity was associated with ischaemic stroke (HR 1.47 [1.00 to 2.16], p=0.05).
Microcalcification in aortopathy: histology study
Thoracic aortopathies are associated with microcalcification which has the potential to be visualised non-invasively using 18F-sodium fluoride positron emission tomography. Thoracic aortic samples were collected from 75 patients with thoracic aortopathy and 19 control samples. Histopathological score, immunohistochemistry and nanoindentation were compared to the extent of microcalcification on histology (von Kossa staining) and autoradiography (18F-sodium fluoride activity). Compared to control samples (0.79 [0.36 to 1.90]), microcalcification content was higher in samples with mild (n=28; 6.17 [2.71 to 10.39], p≤0.00010) or moderate (n=30; 3.74 [0.87, to 11.80], p<0.042), but not severe (n=24; 0.40 [0.15 to 0.87], p=0.42) aortopathy. Microcalcification content was associated with tissue elastic modulus (n=28; r=0.43, p=0.026) and osteopontin staining across all severities of aortopathy (2 p=0.001). Severe aortopathy had substantially less microcalcification compared with mild (p<0.0001) or moderate aortopathy (p=0.00030), and this was closely linked with elastin fragmentation and loss (n=82; r=-0.36, p=0.001). Histological microcalcification demonstrated very good correlation with microcalcification quantified using 18F-sodium fluoride autoradiography (n=66; r=0.76, p<0.001).
Microcalcification in aortopathy: imaging study
Translating the results of the histological study, the relationship between thoracic aortic aneurysm 18F-sodium fluoride activity, diameter, and stiffness was assessed using 18F-sodium fluoride PET-CT, MRI and applanation tonometry in 75 patients with bicuspid aortic valve and 18 controls without aortic disease. Patients with bicuspid aortic valve had higher ascending aortic 18F- sodium fluoride activity than age and sex-matched control subjects (1.10±0.06 versus 1.06±0.08, p=0.046), but similar aortic arch 18F- sodium fluoride activity (1.09±0.11 versus 1.06±0.08, p=0.21). Maximal indexed aortic diameter correlated with ascending aortic 18F-sodium fluoride activity (Spearman r=0.24, p=0.018). Ascending aortic 18F-sodium fluoride activity was associated with aneurysm stiffness index after adjustment for age, sex, diabetes status and maximal indexed aortic diameter (ß=14.017, p=0.008). There was a moderate inverse correlation between ascending aortic 18F-sodium fluoride activity and the annualised progression of aortic strain (n=29, Spearman rho = -0.47, p=0.013), but no relationship with progression of aortic diameter (n=29, Spearman rho = 0.14, p=0.47).
CONCLUSION
18F-Sodium fluoride PET can be reproducibly measured in the thoracic aorta and identifies those with aortic wall disease. In patients with established cardiovascular disease, 18F-sodium fluoride PET is associated with atheroma progression as well as the future risk of stroke and could be used to guide preventative therapy. In thoracic aortic aneurysm, 18F-sodium fluoride PET can track the disease activity of the aortic wall and may represent a crucial modality for identifying those at highest risk of devastating complications
Novel applications of positron emission tomography in the non-invasive assessment of cardiovascular disease
No full textIntroduction.
Fused Positron Emission Tomography and Computed Tomography (PET/CT) is an
emerging investigative tool in cardiovascular disease that provides an imaging-based
quantification of pathophysiological processes of interest. The purpose of this thesis
was to study the application of PET to identify fundamental pathophysiological
processes driving 3 forms of cardiovascular disease: aortic stenosis, myocardial
infarction, and atherosclerosis.
Methods.
Aortic Stenosis. Patients with a spectrum of calcific aortic valve disease (n=121) who
underwent PET-CT imaging for the identification of valvular calcification (18Ffluoride)
and inflammation (18F-fluorodeoxyglucose, 18F-FDG) underwent serial
imaging and clinical follow-up over 2 years. Baseline imaging findings were compared
with echocardiographic and CT markers of disease progression and clinical outcome.
Myocardial Infarction. Patients underwent PET-CT imaging with 18F-fluciclatide (a
novel αvβ3-selective radiotracer highlighting active angiogenesis, inflammation and
fibrosis) after ST-segment elevation MI (n=21), alongside stable patients with chronic
total occlusion (CTO) of a major coronary vessel (n=7), and healthy volunteers (n=9).
Myocardial radiotracer uptake was compared with clinical and cardiac magnetic
resonance imaging (CMR) markers of infarction and remodeling.
Atherosclerosis. Patients with a spectrum of atherosclerotic disease categorized as
stable or unstable (recent MI) underwent PET/CT imaging with 18F-fluciclatide
(n=46). Thoracic aortic 18F-fluciclatide uptake was compared with aortic
atherosclerotic burden quantified by CT plaque thickness, plaque volume and calcium
scoring.
Histological validation. Tissue from the aortic valve, myocardium and carotid arteries
of study subjects was acquired and examined ex vivo using histology and
autoradiography.
Results.
Aortic Stenosis. Baseline valvular 18F-fluoride uptake correlated strongly with the rate
of progression in AVC (r=0.80, p<0.001) and with haemodynamic progression (mean
aortic valve gradient r=0.32, p=0.001). It emerged as independently associated with
clinical outcome after age and sex-adjustment (HR 1.55 [1.33-1.81], p<0.001). 18F-FDG
demonstrated moderate correlations with disease progression as assessed by CT
(r=0.43, p=0.001) and echocardiography (18F-FDG r=0.30, p=0.001), and was
associated with clinical outcomes independent of age and sex (HR 1.35 [1.16-1.58],
p<0.001). Valvular 18F-fluoride uptake correlated with immunohistochemical
markers of calcification activity. There was no correlation between 18F-FDG uptake
and inflammation.
Myocardial Infarction. 18F-Fluciclatide binding was demonstrated in ex vivo peri-infarct
myocardium and uptake was increased in vivo at sites of acute infarction
compared to remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22
vs 0.85±0.17 respectively, 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 myocardial activity
similar to 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), 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.
Atherosclerosis. 18F-Fluciclatide vascular binding ex vivo co-localised with regions
of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis.
18F-Fluciclatide uptake in vivo correlated with measures of aortic atherosclerotic
burden: plaque thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001)
and the CT aortic calcium score (r=0.37, p=0.01). Patients with recent MI had greater
aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.33 vs 1.21,
p=0.01).
Conclusions.
In a range of cardiovascular diseases, PET-CT can provide insights into key
pathophysiological processes, guide patient risk stratification and prognosis, and
identify important biomarkers of disease activity that can be used for the development
of future therapeutic interventions
EACVI survey on standardization of cardiac chambers quantification by transthoracic echocardiography
No full textAIMS
To evaluate standard reporting of cardiac chambers size and function by transthoracic echocardiography (TTE), the EACVI Scientific Initiatives Committee performed a survey across European centres. In particular, the routine use of three-dimensional echocardiography (3DE) and speckle tracking-derived myocardial deformation imaging (STE) was explored.
METHODS AND RESULTS
A total of 96 European Echocardiography Laboratories from 22 different countries responded to the survey, which consisted of 20 questions. For most of the standard parameters of cardiac chamber size and function, answers from the centres were homogeneous and demonstrated good adherence to current recommendations. In particular, all centres assessed left ventricular (LV) and left atrial (LA) size combining diameter measurements with volumes obtained using the bi-plane Simpson's method. More variability was observed in the measurements of the right heart chambers and thoracic aorta. Interestingly, >90% of centres had access to 3DE and STE; however, the large majority of centres reserved the use of these techniques for selected cases, particularly for the measure of 3D LV volumes and ejection fraction and global longitudinal strain in patients being considered for cardiac device implantation, surgical intervention (valvular heart disease) or screened for cardiotoxicity. Only 10% of centres used 3DE for right ventricular and LA volumes. Also, <30% of the centres used LA strain imaging.
CONCLUSION
In Europe, a good adherence to current recommendations was observed for most of the standard parameters of cardiac chambers quantification by TTE. Advanced echocardiography modalities, such as 3DE and STE, are widely available but used only in selected cases
The year 2022 in the European Heart Journal—Cardiovascular Imaging: Part I
No full textThe European Heart Journal-Cardiovascular Imaging with its over 10 years existence is an established leading multi-modality cardiovascular imaging journal. Pertinent publications including original research, how-to papers, reviews, consensus documents, and in our journal from 2022 have been highlighted in two reports. Part I focuses on cardiomyopathies, heart failure, valvular heart disease, and congenital heart disease and related emerging techniques and technologies
Cardiac magnetic resonance imaging assessment of aortic stenosis to improve clinical care
No full textBackground
Aortic stenosis is the commonest valve disease requiring intervention in the
developed world. Current guideline-based management strategies are based
on historical observational data or expert opinion and may leave many patients
with irreversible myocardial damage and adverse outcomes following valve
intervention. The aims of this thesis are to investigate novel cardiac magnetic
resonance techniques and how they can be applied to improve our decision
making around the timing of valve intervention.
Methods and Results
Cardiac magnetic resonance imaging can detect two forms of myocardial
fibrosis non-invasively; diffuse fibrosis using T1 mapping and replacement
fibrosis with the late gadolinium enhancement technique. I devised a novel
measure of diffuse fibrosis, the indexed extracellular volume (iECV) and
showed that these techniques can be used to divide patients into three
categories according to the type and amount of fibrosis present: no fibrosis,
diffuse fibrosis and replacement fibrosis. Moreover, I demonstrated that there
was evidence of increasing left ventricular decompensation across these three
groups.
How fibrosis and left ventricular hypertrophy change over time has not been
well studied in patients with aortic stenosis. Using serial imaging scans, I
showed that hypertrophy and diffuse fibrosis gradually progress over time,
whilst replacement fibrosis accumulates rapidly once first established.
Following valve replacement, cellular hypertrophy regresses faster than
diffuse fibrosis, but replacement fibrosis appears permanent and irreversible.
I then proceeded to investigate T1 mapping measures in a large international
multicentre cohort of patients with aortic stenosis scheduled for valve
replacement. I showed that extracellular volume-based T1 mapping measures
were comparable across centres and therefore confirmed that multicentre
studies are feasible. Extracellular volume fraction was associated with a
decompensating ventricle and emerged as a powerful independent predictor
of all-cause mortality in this group.
Finally, I investigated the use of novel hybrid magnetic resonance and positron
emission tomography imaging in patients with aortic stenosis, showing that
this technique is feasible and well-tolerated. I tested novel attenuation
correction and motion correction methods and showed that this technique can
offer multiparametric imaging of valve, myocardium and coronary arteries in a
single scan.
Conclusion
I have defined the longitudinal changes in hypertrophy and myocardial fibrosis
in aortic stenosis and validated extracellular volume measures as prognostic
markers in this group. Moreover, I have described novel magnetic resonance
and positron emission tomography techniques and their potential to aid the
clinical assessment of patients with aortic stenosis
Computed tomography and positron emission tomography in the assessment of aortic valve disease
No full textIntroduction
Native and bioprosthetic aortic valve diseases are an increasingly common clinical challenge as a consequence of the ageing demographic and the expansion of new valve technology. In both conditions, there remains substantial scope to broaden our understanding of the pathophysiology, improve diagnostic sensitivity and accuracy, and develop new markers of disease activity with which to measure therapeutic effect. Computed tomography (CT) and positron emission tomography (PET) are non-invasive imaging assessments that combine high resolution anatomical detail with real-time functional information about disease activity, and as such are ideally suited to complement echocardiography in the investigation of native and bioprosthetic aortic valve diseases.
Methods
Aortic Stenosis
Volunteers with aortic stenosis (n=143) across a range of severity underwent echocardiography, CT aortic valve calcium scoring and contrast-enhanced CT angiography. Aortic valve fibrosis and calcification were quantified to produce two novel measures: the fibro-calcific ratio and fibro-calcific burden. From the same study population, a subset of 15 volunteers underwent hybrid 18F-fluoride PET/CT on two separate occasions and we investigated different methods of image analysis to optimise accuracy and reproducibility.
Bioprosthetic Valves
Explanted degenerated bioprosthetic valves (n=16) were examined ex vivo using histopathology and preclinical 18F-fluoride PET/CT. Patients with bioprosthetic aortic valves (n=78) were then recruited into two cohorts, with and without prosthetic valve dysfunction, and underwent in-vivo contrast-enhanced CT angiography, 18F-fluoride PET, and serial echocardiography over 2 years of follow-up.
Results
Aortic Stenosis
Contrast-enhanced CT calcium volume correlated closely with conventional CT calcium score in the aortic valve (r=0.86, p=<0.001). Fibrosis dominated in mild aortic stenosis while calcification dominated in severe stenosis (fibro-calcific ratio: 1.33 [0.91-2.4]) versus 0.53 [0.35-1.05] respectively; p=0.001). Males exhibited more calcium than fibrosis, with the reverse true for females (fibro-calcific ratio: 0.89 [0.45-1.54] versus 1.49 [0.82-5.74] respectively; p=0.001). The fibro-calcific burden demonstrated the strongest correlation with peak aortic-jet velocity (r=0.71, p<0.001), especially in women (r=0.77, p=0.001) where it outperformed CT calcium score (p=0.027). In our investigation of 18F-fluoride-PET/CT, contrast-enhanced, ECG-gated PET/CT provided superior spatial localisation of 18F-fluoride uptake. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in variability from 25% to <10%.
Bioprosthetic Valves
In degenerated bioprosthetic valves ex vivo, calcification was the most prevalent pathological feature (87%), whilst thrombus (40%) and pannus overgrowth (47%) were other common findings. All valves exhibited 18F-fluoride uptake on PET, with a strong positive correlation between 18F-fluoride uptake and calcium volume (r=0.73, p=0.0031). 18F-Fluoride uptake was highest in regions of leaflet calcification but also localised to regions of organised thrombus, fibrosis and features of matrix degradation on histopathology.
In the cohort study of patients with bioprosthetic aortic valves, all those with recognised valve dysfunction exhibited abnormalities on CT and high 18F-fluoride uptake. In the 71 patients without valve dysfunction, 20% had leaflet pathology on CT and 34% had increased 18F-fluoride uptake (target-to-background ratio 1.55 [1.44-1.88]). Patients with increased 18F-fluoride uptake exhibited more rapid deterioration in valve function than those without (annualised change in peak transvalvular velocity: 0.30 [0.13-0.61] versus 0.01 [-0.05-0.16] ms-1/year, p<0.001). 18F-Fluoride uptake correlated with deterioration in all echocardiographic measures of valve function (e.g. change in peak velocity, r=0.72; p<0.001) and, on multivariable analysis, was the only independent predictor of future bioprosthetic dysfunction.
Conclusions
In both native aortic valve disease and bioprosthetic valve disease, CT and 18F-fluoride PET afford valuable insights into disease mechanisms, inform patient risk stratification and prognosis, and provide biomarkers of disease activity that may be used for the development of future therapeutic interventions
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