Cardiac 2-D Shear Wave Imaging Using a New Dedicated Clinical Ultrasound System: A Phantom Study.

OBJECTIVE: The purpose of this study was to assess cardiac shear wave imaging implemented in a new MACH 30 ultrasound machine (SuperSonic Imaging, Aix-en-Provence, France) and interfaced with a linear probe and a phased array probe, in comparison with a previously validated Aixplorer system connected to a linear probe (SuperSonic Imaging) using Elasticity QA phantoms (Models 039 and 049, CIRS Inc., Norfolk, VA, USA). METHODS: Quantile-quantile plots were used for distribution agreement. The accuracy of stiffness measurement was assessed by the percentage error and the mean percentage error (MPE), and its homogeneity, by the standard deviation of the MPE. A p value <0.01 was considered to indicate statistical significance. RESULTS: The accuracy of dedicated cardiac sequences for linear probes was similar for the two systems with an MPE of 8 ± 14% versus 20 ± 21% (p = not significant) with the SuperSonic MACH 30 and Aixplorer, respectively, and was influenced by target stiffness and location of the measurement in the field of view, but without drift over time. The optimal transthoracic cardiac probe workspace was located between 4 and 10 cm, with an MPE of 29.5 ± 25% compared with 93.3 ± 130% outside this area (p < 0.0001). In this area, stiffness below 20 kPa was significantly different from the reference (p < 0.0001). The sectorial probe revealed no MPE difference in any of the measurement areas, with no significant lateral or axial gradient. CONCLUSION: The new Supersonic MACH 30 system upgraded with a sectorial probe and specific cardiac settings provided homogenous stiffness measurements, especially when operating at depths between 4 and 10 cm. These phantom results may be useful in designing future in vivo studies.

[18F]FDG PET-MR characterization of aortitis in the IL1rn-/- mouse model of giant-cell arteritis.

BACKGROUND: Metabolic imaging is routinely used to demonstrate aortitis in patients with giant-cell arteritis. We aimed to investigate the preclinical model of aortitis in BALB/c IL1rn-/- mice using [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography-magnetic resonance (PET-MR), gamma counting and immunostaining. We used 15 first-generation specific and opportunistic pathogen-free (SOPF) 9-week-old IL1rn-/- mice, 15 wild-type BALB/cAnN mice and 5 s-generation specific pathogen-free (SPF) 9-week-old IL1rn-/-. Aortic [18F]FDG uptake was assessed as the target-to-background ratio (TBR) using time-of-flight MR angiography as vascular landmarks. RESULTS: [18F]FDG uptake measured by PET or gamma counting was similar in the first-generation SOPF IL1rn-/- mice and the wild-type group (p > 0.05). However, the first-generation IL1rn-/- mice exhibited more interleukin-1ß (p = 0.021)- and interleukin-6 (p = 0.019)-positive cells within the abdominal aorta than the wild-type mice. In addition, the second-generation SPF group exhibited significantly higher TBR (p = 0.0068) than the wild-type mice on the descending thoracic aorta, unlike the first-generation SOPF IL1rn-/- mice. CONCLUSIONS: In addition to the involvement of interleukin-1ß and -6 in IL1rn-/- mouse aortitis, this study seems to validate [18F]FDG PET-MR as a useful tool for noninvasive monitoring of aortitis in this preclinical model.

Targeted Radiation Exposure Induces Accelerated Aortic Valve Remodeling in ApoE-/- Mice.

Thoracic radiation therapy may result in accelerated atherosclerosis and in late aortic valve stenosis (AS). In this study, we assessed the feasibility of inducing radiation-induced AS using a targeted aortic valve irradiation (10 or 20 Grays) in two groups of C57Bl6/J (WT) and ApoE-/- mice compared to a control (no irradiation). Peak aortic jet velocity was evaluated by echocardiography to characterize AS. T2*-weighted magnetic resonance imaging after injection of MPIO-αVCAM-1 was used to examine aortic inflammation resulting from irradiation. A T2* signal void on valve leaflets and aortic sinus was considered positive. Valve remodeling and mineralization were assessed using von Kossa staining. Finally, the impact of radiation on cell viability and cycle from aortic human valvular interstitial cells (hVICs) was also assessed. The targeted aortic valve irradiation in ApoE-/- mice resulted in an AS characterized by an increase in peak aortic jet velocity associated with valve leaflet and aortic sinus remodeling, including mineralization process, at the 3-month follow-up. There was a linear correlation between histological findings and peak aortic jet velocity (r = 0.57, p < 0.01). In addition, irradiation was associated with aortic root inflammation, evidenced by molecular MR imaging (p < 0.01). No significant effect of radiation exposure was detected on WT animals. Radiation exposure did not affect hVICs viability and cell cycle. We conclude that targeted radiation exposure of the aortic valve in mice results in ApoE-/-, but not in WT, mice in an aortic valve remodeling mimicking the human lesions. This preclinical model could be a useful tool for future assessment of therapeutic interventions.

Measuring myocardial blood flow using dynamic myocardial perfusion SPECT: artifacts and pitfalls.

Dynamic acquisition allows absolute quantification of myocardial perfusion and flow reserve, offering an alternative to overcome the potential limits of relative quantification, especially in patients with balanced multivessel coronary artery disease. SPECT myocardial perfusion is widely available, at lower cost than PET. Dynamic cardiac SPECT is now feasible and has the potential to be the next step of comprehensive perfusion imaging. In order to help nuclear cardiologists potentially interested in using dynamic perfusion SPECT, we sought to review the different steps of acquisition, processing, and reporting of dynamic SPECT studies in order to enlighten the potentially critical pitfalls and artifacts. Both patient-related and technical artifacts are discussed. Key parameters of the acquisition include pharmacological stress, radiopharmaceuticals, and injection device. When it comes to image processing, attention must be paid to image-derived input function, patient motion, and extra-cardiac activity. This review also mentions compartment models, cameras, and attenuation correction. Finally, published data enlighten some facets of dynamic cardiac SPECT while several issues remain. Harmonizing acquisition and quality control procedures will likely improve its performance and clinical strength.

Relationship between lifestyle factors and hypertension: a cross-sectional analysis from the Gubbio study.

BACKGROUND: Hypertension (HTN) is a well-established and a major risk factor for cardiovascular disease. Lifestyle behaviours for its prevention and control are recommended within worldwide guidelines. Their relationship with HTN need more investigations. AIM: We aimed to investigate the associations between lifestyle, anthropometric and biological measurements and BP in the Gubbio residential study. METHODS: Cross-sectional analyses were performed using data from Gubbio study. Information concerning lifestyle factors were collected using self-reported questionnaire and were further completed with a baseline clinical examination and blood exams. Three BP measurements were performed following a standard protocol. Age-adjusted and multivariable logistic regressions were used to examine the relationships between lifestyle parameters and HTN separately for each sex. We used heterogeneity test to observe sex differences. RESULTS: There were 3,183 persons included (48% men, 43 ± 17 years old). Mean systolic BP (SBP) was 119 ± 16 mmHg and 10.6% were hypertensives. Age [OR: 129.70 (95%CI: 18.57-905.79) in women and OR: 8.37 (95%CI: 4.01-17.48) (p < 0.0001) in men] and BMI [OR: 2.14 (95%CI: 1.32-3.46) (p = 0.006) in women and OR: 1.81 (95%CI: 1.05-3.12), p = 0.03 in men], were positively associated with SBP in both sexes. Serum uric acid [OR: 3.86 (95%CI: 2.03-7.26), p = 0.04] was positively associated with HTN in women while fasting blood glucose [OR: 3.04 (95%CI: 1.55-5.97), p < 0.001] were associated to HTN only in men. DISCUSSION: In addition to age, BMI is associated with HTN in both sexes while sex differences were observed in the associations between serum uric acid, fasting blood glucose and HTN.

Left atrial strain quantified after myocardial infarction is associated with early left ventricular remodeling.

BACKGROUND: Left ventricular remodeling (LVR) is common and associated with adverse outcome after ST-elevation myocardial infarction (STEMI). We aimed to investigate the association between left atrial (LA) mechanical function using speckle tracking imaging and early LVR at follow-up in STEMI patients. METHODS: Baseline 3D thoracic echocardiograms were performed within 48 h following admission and at a median follow-up of 7 months after STEMI. A > 20% increase in the left ventricular (LV) end-diastolic volume compared to baseline at follow-up was defined as LVR. LA global longitudinal strain was evaluated for the reservoir, conduit, and contraction (LASct) phases. RESULTS: A total of 121 patients without clinical heart failure (HF) were prospectively included, between June 2015 and October 2018 (age 58.3 ± 12.5 years, male 98 (81%)). Baseline and follow-up LV ejection fraction (LVEF) were 46.8% [41.0, 52.9] and 52.1% [45.8, 57.0] respectively (p < .001). Compared to other patients, those with LVR had significantly lower values of LASct at baseline (-7.4% [-10.1, -6.5] vs. -9.9% [-12.8, -8.1], p < .01), both on univariate and baseline LV volumes-adjusted analyses. Baseline LA strain for reservoir and conduit phases were not associated with significant LVR at follow-up. Intra- and interobserver analysis showed good reproducibility of LA strain. CONCLUSIONS: Baseline LASct may help identifying patients without HF after STEMI who are at higher risk of further early LVR and subsequent HF and who may benefit from more intensive management.

TRPM4 Participates in Irradiation-Induced Aortic Valve Remodeling in Mice.

Thoracic radiotherapy can lead to cardiac remodeling including valvular stenosis due to fibrosis and calcification. The monovalent non-selective cation channel TRPM4 is known to be involved in calcium handling and to participate in fibroblast transition to myofibroblasts, a phenomenon observed during aortic valve stenosis. The goal of this study was to evaluate if TRPM4 is involved in irradiation-induced aortic valve damage. Four-month-old Trpm4+/+ and Trpm4-/- mice received 10 Gy irradiation at the aortic valve. Cardiac parameters were evaluated by echography until 5 months post-irradiation, then hearts were collected for morphological and histological assessments. At the onset of the protocol, Trpm4+/+ and Trpm4-/- mice exhibited similar maximal aortic valve jet velocity and mean pressure gradient. Five months after irradiation, Trpm4+/+ mice exhibited a significant increase in those parameters, compared to the untreated animals while no variation was detected in Trpm4-/- mice. Morphological analysis revealed that irradiated Trpm4+/+ mice exhibited a 53% significant increase in the aortic valve cusp surface while no significant variation was observed in Trpm4-/- animals. Collagen staining revealed aortic valve fibrosis in irradiated Trpm4+/+ mice but not in irradiated Trpm4-/- animals. It indicates that TRPM4 influences irradiation-induced valvular remodeling.

Quantitation of myocardial 99mTc-HMDP uptake with new SPECT/CT cadmium zinc telluride (CZT) camera in patients with transthyretin-related cardiac amyloidosis: Ready for clinical use?

BACKGROUND: The aim of this study was to investigate the feasibility of assessing absolute myocardial 99mTc-HMDP uptake in patients with suspected cardiac ATTR using SUV with a whole-body CZT SPECT-CT camera (DNM670CZT). METHODS: Fifteen patients with suspected cardiac ATTR (Perugini ≥ 2) underwent a conventional 99mTc-HMDP planar imaging and a thoracic SPECT/CT using a DNM 670CZT. A control group consisted of 15 patients with negative scintigraphy (Perugini < 2). SUVmax (mg·L-1) and percentage of injected dose (%ID) were calculated in a cardiac volume of interest (VOI) encompassing the left ventricle. VOIs were also placed in the lung, the right pectoris major, and the sternum. A heart-to-lung SUVmax ratio (HLR) was calculated. RESULTS: All ATTR patients demonstrated an increased cardiac HMDP SUVmax (12.2 ± 3.7 mg·L-1) vs controls (3.5 ± 1.2, P < .0001). Percentage of ID, pectoral uptake and HLR were significantly higher in the ATTR group (1.1 ± 0.3 vs 0.15 ± 0.8, P < .0001; 1.5 ± 0.3 vs 0.9 ± 0.3, P < .0001; 9.7 ± 3 vs 4.3 ± 2.2, P < .0001). Bone uptake was not statistically different between the two groups. CONCLUSION: This study demonstrated the feasibility of quantitative 99mTc-HMDP SUVmax measurement using a whole-body SPECT/CT CZT camera in patients with suspected cardiac ATTR.

Definition of left ventricular remodelling following ST-elevation myocardial infarction: a systematic review of cardiac magnetic resonance studies in the past decade.

An increase in left ventricular volumes between baseline and follow-up imaging is the main criteria for the quantification of left ventricular remodelling (LVR) after ST-elevation myocardial infarction (STEMI), but without consensual definition. We aimed to review the criteria used for the definition of LVR based on cardiac magnetic resonance imaging (CMR) in STEMI patients. A systematic literature search was conducted using MEDLINE and the Cochrane Library from January 2010 to August 2019. Thirty-seven studies involving 4209 patients were included. Among these studies, 30 (81%) used a cut-off value for defining LVR, with a pooled LVR prevalence estimate of 22.8%, 95% CI [19.4-26.7%] and a major between-study heterogeneity (I2 = 82%). The seven remaining studies (19%) defined LVR as a continuous variable. The definition of LVR using CMR following STEMI is highly variable, among studies including highly selected patients. A 20% increase or a 15% increase in left ventricular volumes between a baseline and a follow-up CMR imaging were the two most common criterion (13 [35%] and 9 [24%] studies, respectively). The most frequent LVR criterion was a 20% increase in end-diastolic volumes or a 15% increase in end-systolic volumes. A composite cut-off value of a 12 to 15% increase in end-systolic volume and a 12 to 20% increase in end-diastolic volume using a follow-up CMR imaging 3 months after STEMI might be proposed as a consensual cut-off for defining adverse LVR for future large-sized, prospective studies with serial CMR imaging and long-term follow-up in unselected patients.

Evaluation of the early-phase [18F]AV45 PET as an optimal surrogate of [18F]FDG PET in ageing and Alzheimer's clinical syndrome.

Dual-phase [18F]AV45 positron emission tomography (PET) is highly promising in the assessment of neurodegenerative diseases, allowing to obtain information on both neurodegeneration (early-phase; eAV45) and amyloid deposition (late-phase; lAV45) which are highly complementary; yet eAV45 needs further evaluation. This study aims at validating eAV45 as an optimal proxy of [18F]FDG PET in a large mixed-population of healthy ageing and Alzheimer's clinical syndrome participants (n = 191) who had [18F]FDG PET, eAV45 and lAV45 scans. We found early time frame 0-4 min to give maximal correlation with [18F]FDG PET and minimal correlation with lAV45. Moreover, maximal overlap of [18F]FDG PET versus eAV45 associations with clinical diagnosis and cognition was obtained with pons scaling. Across reference regions, classification performance between clinical subgroups was similar for both eAV45 and [18F]FDG PET. These findings highlight the optimal use of eAV45 to assess neurodegeneration as a validated proxy of [18F]FDG PET. On top of this purpose, this study showed that combined [18F]AV45 PET dual-biomarker even outperformed [18F]FDG PET or lAV45 alone.

First Follow-Up of Cardiac Amyloidosis Treated by Tafamidis, Evaluated by Absolute Quantification in Bone Scintigraphy.

Assessment of absolute myocardial hydroxydimethylene diphosphonate-technetium-99m uptake using standardized uptake value with a single-photon emission computed tomography-computed tomography cadmium zinc telluride camera (Discovery NM/CT 670CZT, GE Healthcare, Chicago, Illinois) in a patient with cardiac transthyretin-related amyloidosis treated with tafamidis showed a decrease in hydroxydimethylene diphosphonate cardiac uptake. This imaging technique should be helpful in monitoring therapy and evaluating prognosis. (Level of Difficulty: Intermediate.).

TRPM4 Participates in Aldosterone-Salt-Induced Electrical Atrial Remodeling in Mice.

Aldosterone plays a major role in atrial structural and electrical remodeling, in particular through Ca2+-transient perturbations and shortening of the action potential. The Ca2+-activated non-selective cation channel Transient Receptor Potential Melastatin 4 (TRPM4) participates in atrial action potential. The aim of our study was to elucidate the interactions between aldosterone and TRPM4 in atrial remodeling and arrhythmias susceptibility. Hyperaldosteronemia, combined with a high salt diet, was induced in mice by subcutaneously implanted osmotic pumps during 4 weeks, delivering aldosterone or physiological serum for control animals. The experiments were conducted in wild type animals (Trpm4+/+) as well as Trpm4 knock-out animals (Trpm4-/-). The atrial diameter measured by echocardiography was higher in Trpm4-/- compared to Trpm4+/+ animals, and hyperaldosteronemia-salt produced a dilatation in both groups. Action potentials duration and triggered arrhythmias were measured using intracellular microelectrodes on the isolated left atrium. Hyperaldosteronemia-salt prolong action potential in Trpm4-/- mice but had no effect on Trpm4+/+ mice. In the control group (no aldosterone-salt treatment), no triggered arrythmias were recorded in Trpm4+/+ mice, but a high level was detected in Trpm4-/- mice. Hyperaldosteronemia-salt enhanced the occurrence of arrhythmias (early as well as delayed-afterdepolarization) in Trpm4+/+ mice but decreased it in Trpm4-/- animals. Atrial connexin43 immunolabelling indicated their disorganization at the intercalated disks and a redistribution at the lateral side induced by hyperaldosteronemia-salt but also by Trpm4 disruption. In addition, hyperaldosteronemia-salt produced pronounced atrial endothelial thickening in both groups. Altogether, our results indicated that hyperaldosteronemia-salt and TRPM4 participate in atrial electrical and structural remodeling. It appears that TRPM4 is involved in aldosterone-induced atrial action potential shortening. In addition, TRPM4 may promote aldosterone-induced atrial arrhythmias, however, the underlying mechanisms remain to be explored.

Steroid-sparing effect of anakinra in giant-cell arteritis: a case series with clinical, biological and iconographic long-term assessments.

OBJECTIVES: The treatment of GCA relies on corticosteroids but is burdened by a high rate of relapses and adverse effects. Anti-IL-6 treatments show a clear benefit with a significant steroid-sparing effect, but late relapses occur after treatment discontinuation. In addition to IL-6, IL-1 also appears to play a significant role in GCA pathophysiology. We report herein the efficacy of anakinra, an IL-1 receptor antagonist, in six GCA patients exhibiting corticosteroid dependence or resistance, specifically analysing the outcome of aortitis in four of them. METHODS: This retrospective study analysed the cases of all GCA patients treated with anakinra from the French Study Group for Large Vessel Vasculitis. RESULTS: After a median duration of anakinra therapy of 19 (18-32) months, all six patients exhibited complete clinical and biological remission. Among the four patients with large-vessel involvement, one had a disappearance of aortitis under anakinra and three showed a decrease in vascular uptake. After a median follow-up of 56 (48-63) months, corticosteroids were discontinued in four patients, and corticosteroid dosage could be decreased to 5 mg/day in two patients. One patient relapsed 13 months after anakinra introduction in the context of increasing the daily anakinra injection interval to every 48 h. Three patients experienced transient injection-site reactions, and one patient had pneumonia. CONCLUSION: In this short series, anakinra appears to be an efficient and safe steroid-sparing agent in refractory GCA, with a possible beneficial effect on large-vessel involvement.

Quantification of myocardial blood flow by CZT-SPECT with motion correction and comparison with 15O-water PET.

BACKGROUND: We compared quantification of MBF and myocardial flow reserve (MFR) with a 99mTc-sestamibi CZT-SPECT to 15O-water PET. METHODS: SPECT MBF for thirty patients in the WATERDAY study was re-analyzed by QPET software with motion correction and optimal placement of the arterial input function. 15O-water PET MBF was re-quantified using dedicated software. Inter-operator variability was assessed using repeatability coefficients (RPC). RESULTS: Significant correlations were observed between global (r = 0.91, P < 0.001) and regional MBF (r = 0.86, P < 0.001) with SPECT compared to PET. Global MBF (rest 0.95 vs 1.05 ml/min/g, P = 0.07; stress 2.62 vs 2.68 mL/min/g, P = 0.17) and MFR (2.65 vs 2.75, P = 0.86) were similar between SPECT and PET. Rest (0.81 vs 0.98 mL/min/g, P = 0.03) and stress MBF (1.98 vs 2.61 mL/min/g, P = 0.01) in right coronary artery (RCA) were lower with SPECT compared to PET. However, MFR in the RCA territory was similar (2.54 vs 2.77, P = 0.21). The SPECT-PET RPC for global MBFs and MFR were 0.95 mL/min/g and 0.94, with inter-observer RPC of 0.59 mL/min/g and 0.74, respectively. CONCLUSIONS: MBF and MFR derived from CZT-SPECT with motion correction and optimal placement of the arterial input function showed good agreement with 15O-water PET, as well as low inter-operator variability.

Impaired left atrial function in adults and adolescents with corrected aortic coarctation.

This study examined the left atrial (LA) function using two-dimensional (2D) strain analysis after aortic coarctation (CoA) repair, as well as relationships between LA function and patient characteristics, especially aortic arch anatomy. 56 patients (34 males, age: 31 ± 16 years) with CoA repair (46 post 'end-to-end anastomosis/subclavian flap') and 56 controls were studied. 2D strain imaging was performed to assess left ventricular (LV) and LA functions including peak-positive LA strain, early and late diastolic LA strains, and global longitudinal (LV-GLS) and circumferential (LV-GCS) strains. LA dysfunction (LAD) was defined as a peak-positive LA strain value lower than the mean value of the control group minus 2 SDs. Peak-positive LA strain, early and late diastolic LA strains, and LV-GLS were significantly lower in the CoA group while LV-GCS did not differ. No significant correlation was found between LA strain and either current age, age at initial repair, or blood pressure; Ea and LV-GLS were moderately correlated to peak-positive LA strain (r = 0.49, p < 0.001 and r = - 0.55, p < 0.001, respectively). 23 CoA patients (41%) presented LAD (abnormal peak-positive LA strain < 25%). Among patients who underwent end-to-end anastomosis/subclavian flap, those with a non-romanesque aortic arch anatomy exhibited a significantly lower peak-positive LA strain. Ischemic stroke and atrial arrhythmia were more frequent in CoA patients with LAD. Our findings suggest that LAD may be prevalent late after CoA repair. Postoperative aortic arch anatomy may impact peak-positive LA strain.

TRPM4 non-selective cation channel in human atrial fibroblast growth.

Cardiac fibroblasts play an important role in cardiac matrix turnover and are involved in cardiac fibrosis development. Ca2+ is a driving belt in this phenomenon. This study evaluates the functional expression and contribution of the Ca2+-activated channel TRPM4 in atrial fibroblast phenotype. Molecular and electrophysiological investigations were conducted in human atrial fibroblasts in primary culture and in atrial fibroblasts obtained from wild-type and transgenic mice with disrupted Trpm4 gene (Trpm4-/-). A typical TRPM4 current was recorded on human cells (equal selectivity for Na+ and K+, activation by internal Ca2+, voltage sensitivity, conductance of 23.2 pS, inhibition by 9-phenanthrol (IC50 = 6.1 × 10-6 mol L-1)). Its detection rate was 13% on patches at days 2-4 in culture but raised to 100% on patches at day 28. By the same time, a cell growth was observed. This growth was smaller when cells were maintained in the presence of 9-phenanthrol. Similar cell growth was measured on wild-type mice atrial fibroblasts during culture. However, this growth was minimized on Trpm4-/- mice fibroblasts compared to control animals. In addition, the expression of alpha smooth muscle actin increased during culture of atrial fibroblasts from wild-type mice. This was not observed in Trpm4-/- mice fibroblasts. It is concluded that TRPM4 participates in fibroblast growth and could thus be involved in cardiac fibrosis.

An overview of the perspectives on experimental models and new therapeutic targets in giant cell arteritis.

Giant cell arteritis (GCA) is the most frequent systemic vasculitis occurring in adults older than 50 years, and aortitis is described in 40% to 80% of patients. The treatment relies on corticosteroids, but it is complicated by high rates of relapses and adverse effects and may be unable to completely inhibit aortic inflammation. Moreover, most of the current data regarding the pathophysiology of GCA have been obtained from bioassays using blood and temporal arteries, as well as histological analyses of temporal arteries and very few aortic aneurysms from patients with GCA. The limitations of these analyses prevent researchers from determining the implications of specific targets and studying the effects of targeted treatments. Several experimental models have been developed, but to date, a perfect model is not available for GCA, particularly for studies of large-vessel vasculitis. The review focuses on the perspectives on experimental models and new therapeutic targets in giant cell arteritis.