Cardiovascular magnetic resonance and positron emission tomography in the assessment of aortic stenosis

Background 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

Evidence for a relatively high proportion of DM2 mutations in a large group of Polish patients

Introduction: Myotonic dystrophies (DMs) type 1 (DM1) and type 2 (DM2) are autosomal dominant, multisystem disorders, considered the most common dystrophies in adults. DM1 and DM2 are caused by dynamic mutations in the DMPK and CNBP genes, respectively. Methods: Molecular analyses were performed by PCR and the modified RP-PCR in patients, in their at-risk relatives and prenatal cases. Results: The analysis of Polish controls revealed the range of 5-31 CTG repeats for DM1 and 110-228 bp alleles for DM2. Among 318 confirmed probands - 196 (62%) were DM1 and 122 (38%) – DM2. Within DM1families, 10 subjects carried a low expanded CTG tract (&lt; 100 repeats), which resulted in a full mutation in subsequent generations. Two related individuals had unstable alleles–188 bp and 196 bp without common interruptions. Conclusion: The relative frequencies of DM1/DM2 among Polish patients were 68% and 32%, respectively, with a relatively high proportion of DM2 mutations (1.6:1)

Aortic valve imaging using 18F-sodium fluoride: impact of triple motion correction

BACKGROUND: Current (18)F-NaF assessments of aortic valve microcalcification using (18)F-NaF PET/CT are based on evaluations of end-diastolic or cardiac motion-corrected (ECG-MC) images, which are affected by both patient and respiratory motion. We aimed to test the impact of employing a triple motion correction technique (3 × MC), including cardiorespiratory and gross patient motion, on quantitative and qualitative measurements. MATERIALS AND METHODS: Fourteen patients with aortic stenosis underwent two repeat 30-min PET aortic valve scans within (29 ± 24) days. We considered three different image reconstruction protocols; an end-diastolic reconstruction protocol (standard) utilizing 25% of the acquired data, an ECG-gated (four ECG gates) reconstruction (ECG-MC), and a triple motion-corrected (3 × MC) dataset which corrects for both cardiorespiratory and patient motion. All datasets were compared to aortic valve calcification scores (AVCS), using the Agatston method, obtained from CT scans using correlation plots. We report SUV(max) values measured in the aortic valve and maximum target-to-background ratios (TBR(max)) values after correcting for blood pool activity. RESULTS: Compared to standard and ECG-MC reconstructions, increases in both SUV(max) and TBR(max) were observed following 3 × MC (SUV(max): Standard = 2.8 ± 0.7, ECG-MC = 2.6 ± 0.6, and 3 × MC = 3.3 ± 0.9; TBR(max): Standard = 2.7 ± 0.7, ECG-MC = 2.5 ± 0.6, and 3 × MC = 3.3 ± 1.2, all p values ≤ 0.05). 3 × MC had improved correlations (R(2) value) to the AVCS when compared to the standard methods (SUV(max): Standard = 0.10, ECG-MC = 0.10, and 3 × MC = 0.20; TBR(max): Standard = 0.20, ECG-MC = 0.28, and 3 × MC = 0.46). CONCLUSION: 3 × MC improves the correlation between the AVCS and SUV(max) and TBR(max) and should be considered in PET studies of aortic valves using (18)F-NaF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40658-022-00433-7

Feasibility of Coronary 18F-Sodium Fluoride Positron-Emission Tomography Assessment With the Utilization of Previously Acquired Computed Tomography Angiography

BACKGROUND: We assessed the feasibility of utilizing previously acquired computed tomography angiography (CTA) with subsequent positron-emission tomography (PET)-only scan for the quantitative evaluation of 18F-NaF PET coronary uptake. METHODS AND RESULTS: 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 1 with 18F-NaF PET (PET) from visit 2 and compared visual pattern of activity, maximal standard uptake (SUVmax) values, and target to background ratio (TBR) measurements on (PET/CTA1) fused versus hybrid (PET/CTA2). On PET/CTA2, 226 coronary plaques were identified. Fifty-eight coronary segments from 28 (62%) patients had high 18F-NaF uptake (TBR >1.25), whereas 168 segments had lesions with 18F-NaF TBR ≤1.25. Uptake in all lesions was categorized identically on coregistered PET/CTA1. There was no significant difference in 18F-NaF uptake values between PET/CTA1 and PET/CTA2 (SUVmax, 1.16±0.40 versus 1.15±0.39; P=0.53; TBR, 1.10±0.45 versus 1.09±0.46; P=0.55). The intraclass correlation coefficient for SUVmax and TBR was 0.987 (95% CI, 0.983-0.991) and 0.986 (95% CI, 0.981-0.992). 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 versus ±0.20 and ±0.20 on diastolic imaging; P<0.001). CONCLUSIONS: Coronary CTA/PET protocol with CTA first followed by PET-only allows for reliable and reproducible quantification of 18F-NaF coronary uptake. This approach may facilitate selection of high-risk patients for PET-only imaging based on results from prior CTA, providing a practical workflow for clinical application.ope

Myocardial Fibrosis and Cardiac Decompensation in Aortic Stenosis

OBJECTIVES: Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality. BACKGROUND: Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis. METHODS: In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m(2)) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up. RESULTS: iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p < 0.001; n = 11) and was increased in patients with aortic stenosis (23.6 ± 7.2 ml/m(2) vs. 16.1 ± 3.2 ml/m(2) in control subjects; p < 0.001). iECV was used together with LGE to categorize patients with normal myocardium (iECV <22.5 ml/m(2); 51% of patients), extracellular expansion (iECV ≥22.5 ml/m(2); 22%), and replacement fibrosis (presence of mid-wall LGE, 27%). There was evidence of increasing hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction consistent with progressive left ventricular decompensation (all p < 0.05) across these groups. Moreover, this categorization was of prognostic value with stepwise increases in unadjusted all-cause mortality (8 deaths/1,000 patient-years vs. 36 deaths/1,000 patient-years vs. 71 deaths/1,000 patient-years, respectively; p = 0.009). CONCLUSIONS: CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis; NCT01755936)

Triple-gated motion and blood pool clearance corrections improve reproducibility of coronary 18F-NaF PET

PurposeTo improve the test-retest reproducibility of coronary plaque 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) uptake measurements.MethodsWe recruited 20 patients with coronary artery disease who underwent repeated hybrid PET/CT angiography (CTA) imaging within 3&nbsp;weeks. All patients had 30-min PET acquisition and CTA during a single imaging session. Five PET image-sets with progressive motion correction were reconstructed: (i) a static dataset (no-MC), (ii) end-diastolic PET (standard), (iii) cardiac motion corrected (MC), (iv) combined cardiac and gross patient motion corrected (2 × MC) and, (v) cardiorespiratory and gross patient motion corrected (3 × MC). In addition to motion correction, all datasets were corrected for variations in the background activities which are introduced by variations in the injection-to-scan delays (background blood pool clearance correction, BC). Test-retest reproducibility of PET target-to-background ratio (TBR) was assessed by Bland-Altman analysis and coefficient of reproducibility.ResultsA total of 47 unique coronary lesions were identified on CTA. Motion correction in combination with BC improved the PET TBR test-retest reproducibility for all lesions (coefficient of reproducibility: standard = 0.437, no-MC = 0.345 (27% improvement), standard&nbsp;+&nbsp;BC = 0.365 (20% improvement), no-MC + BC = 0.341 (27% improvement), MC + BC = 0.288 (52% improvement), 2 × MC + BC = 0.278 (57% improvement) and 3 × C + BC = 0.254 (72% improvement), all p &lt; 0.001). Importantly, in a sub-analysis of 18F-NaF-avid lesions with gross patient motion &gt;&nbsp;10&nbsp;mm following corrections, reproducibility was improved by 133% (coefficient of reproducibility: standard = 0.745, 3 × MC = 0.320).ConclusionJoint corrections for cardiac, respiratory, and gross patient motion in combination with background blood pool corrections markedly improve test-retest reproducibility of coronary 18F-NaF PET