Evaluation of the Specificity of the 2023 Duke-International Society of Cardiovascular Infectious Diseases Classification for Infective Endocarditis.

BACKGROUND: The 2023 Duke-ISCVID (International Society of Cardiovascular Infectious Diseases) classification is a new diagnostic tool for infective endocarditis, updating the 2000 modified Duke and the 2015 European Society for Cardiology (ESC) classifications. In comparison, its sensitivity is higher; however, its specificity remains to be evaluated and compared to that of the 2 other classifications in endocarditis suspected patients. METHODS: We retrospectively collected the characteristics of patients hospitalized in Bichat University's Hospital, Paris, in 2021, who had been evaluated for clinical suspicion of endocarditis, have had at least a transthoracic echocardiography, 2 pairs of blood cultures, 3-month follow-up and in whom endocarditis diagnosis was finally rejected. All patients were classified by 2000 modified Duke, 2015 ESC and 2023 Duke-ISCVID, as though the endocarditis diagnosis had not been rejected. RESULTS: In total, 130 patients' charts were analyzed. Mean age was 62 years, 84 (64.6%) were male, 39 (30.0%) had prosthetic cardiac valve or valve repair, 21 (16.2%) cardiac implanted electronic device, and 30 (23.1%) other cardiac conditions. Overall, 5, 2, and 5 patients were falsely classified as definite endocarditis with the 2000 modified Duke, 2015 ESC, and 2023 Duke-ISCVID classifications, respectively. The corresponding specificities were 96.2% (95% confidence interval [CI] [90.8%, 98.6%]), 98.5% (95% CI [93.9%, 99.7%]), and 96.2% (95% CI [90.8%, 98.6%]). The rates of possible endocarditis were of 38%, 35%, and 35% in the 3 classifications, respectively. CONCLUSIONS: The 2023 Duke-ISCVID classification is highly specific for ruling out the diagnosis of definite infective endocarditis in patients who had been evaluated for IE.

Detailed clinical, physiological and pathological phenotyping can impact access to disease-modifying treatments in ATTR carriers.

BACKGROUND: Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant systemic disease due to pathogenic TTR variants (ATTRv), mostly affecting the peripheral nerves and heart. The disease is characterised by a combination of symptoms, organ involvement and histological amyloid deposition. The available disease-modifying ATTRv treatments (DMTs) are more effective if initiated early. Pathological nerve conduction studies (NCS) results are the cornerstone of large-fibre polyneuropathy diagnosis, but this anomaly occurs late in the disease. We investigated the utility of a multimodal neurological and cardiac evaluation for detecting early disease onset in ATTRv carriers. METHODS: We retrospectively analysed a cohort of ATTRv carriers with normal NCS results regardless of symptoms. Multimodal denervation and infiltration evaluations included a clinical questionnaire (Lauria and New York Heart Association (NYHA)) and examination, intra-epidermal nerve fibre density assessment, autonomic assessment based on heart rate variability, Sudoscan, meta-iodo-benzyl-guanidine scintigraphy, cardiac biomarkers, echocardiography, MRI and searches for amyloidosis on skin biopsy and bone scintigraphy. RESULTS: We included 130 ATTRv carriers (40.8% men, age: 43.6±13.5 years), with 18 amyloidogenic TTR gene mutations, the majority of which was the late-onset Val30Met variant (42.3%). Amyloidosis was detected in 16.9% of mutation carriers, including 9 (6.9%) with overt disease (Lauria>2 or NYHA>1) and 13 asymptomatic carriers (10%) with organ involvement (small-fibre neuropathy or cardiomyopathy). Most of these patients received DMT. Abnormal test results of unknown significance were obtained for 105 carriers (80.8%). Investigations were normal in only three carriers (2.3%). CONCLUSIONS: Multimodal neurological and cardiac investigation of TTRv carriers is crucial for the early detection of ATTRv amyloidosis and initiation of DMT.

Prognosis and follow-up of patients with prosthetic valve endocarditis treated conservatively in relation to WBC-SPECT imaging.

BACKGROUND: Our objective was to evaluate in patients with prosthetic valve endocarditis (PVE) treated conservatively, the prognostic value of white blood cell (WBC) signal intensity on SPECT and to describe the evolution of the WBC signal under antibiotics. METHODS: Patients with PVE treated conservatively and positive WBC-SPECT imaging were identified retrospectively. Signal intensity was classified as intense if equal to or higher, or mild if lower, than the liver signal. Clinical, biological, imaging and follow-up information were collected from medical files. RESULTS: Among 47 patients, WBC signal was classified as intense in 10 patients and as mild, in 37. The incidence of the primary composite endpoint (death, late cardiac surgery, or relapse) was significantly higher in patients with intense vs. mild signal (90% vs. 11%). Twenty-five patients underwent a second WBC-SPECT imaging during follow-up. The prevalence of WBC signal decreased progressively from 89% between 3 and 6 weeks to 42% between 6 and 9 weeks and 8% more than 9 weeks after initiation of antibiotics. CONCLUSIONS: In patients with PVE treated conservatively, intense WBC signal was associated with poor outcome. WBC-SPECT imaging appears as an interesting tool for risk stratification and to monitor locally the efficacy of antibiotic treatment.

Diagnosis and staging of cardiac masses: additional value of CMR with 18F-FDG-PET compared to CMR with CECT.

PURPOSE: Characterization of malignant cardiac masses is usually performed with cardiac magnetic resonance (CMR) and staging with whole-body contrast-enhanced computed tomography (CECT). In this study, our objective was to evaluate the role of 18Fluor-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) with CMR for both characterization and staging of cardiac masses. METHODS: Patients with cardiac masses who underwent CMR, CECT, and 18F-FDG-PET were retrospectively identified. For the characterization of cardiac masses, we calculated the respective performances of CMR alone, 18F-FDG-PET alone, and the combination of 18F-FDG-PET and CMR. For staging, we compared head-to-head the respective performances of 18F-FDG-PET and CECT. Histology served as gold standard for malignancy, and response to anticoagulation for thrombus. RESULTS: In a total of 28 patients (median age 60.5 years, 60.7% women), CMR accurately distinguished malignant from benign masses with sensitivity (Se) of 86.7%, specificity (Sp) of 100%, positive predictive value (PPV) of 100%, negative predictive value (NPV) of 86.7%, and accuracy of 92.9%. 18F-FDG-PET demonstrated 93.3% Se, 84.6% Sp, 87.5% PPV, 91.7% NPV, and 89.3% accuracy. Combining CMR with 18F-FDG-PET allowed to benefit from the high sensitivity of 18F-FDG-PET (92.9%) and the excellent specificity of CMR (100%) for malignant diseases. For staging, 18F-FDG-PET outperformed CECT on per-patient (66.7% vs 55.6% correct diagnosis, respectively), per-organ (10 vs 7 organs, respectively), and per-lesion basis (> 29 vs > 25 lesions, respectively). CONCLUSION: Combining 18F-FDG-PET with CMR improved the characterization of cardiac masses compared to each modality alone. Additionally, the diagnostic performance of 18F-FDG-PET was better than CECT for staging. This study suggests that the combination of CMR and 18F-FDG-PET is the most effective for the characterization of cardiac masses and the staging of these lesions.

Diagnostic performance of White Blood Cell SPECT imaging against intra-operative findings in patients with a suspicion of prosthetic valve endocarditis.

AIM: The objective of this study was to evaluate the diagnostic performance of white blood cells (WBC)-SPECT imaging in patients with suspicion of prosthetic valve endocarditis (PVE) against intra-operative findings. METHODS: 36 consecutive patients who underwent cardiac surgery 30 days after WBC-SPECT imaging were identified retrospectively. Clinical, imaging, and biological results were collected from reports. WBC-SPECT results were classified as positive or negative and, if positive, the intensity of signal graded as intense or mild. Lesions observed during cardiac surgery were collected from surgeons' reports. RESULTS: The 20 patients with positive WBC-SPECT study had confirmed PVE intra-operatively. Patients with intense signal on WBC-SPECT had high prevalence of abscesses (83%) compared to patients with only mild signal (12%). The three patients with negative WBC-SPECT but confirmed PVE had longer duration of antibiotic treatment before imaging and had no perivalvular abscess. Sensitivity, specificity, positive predictive and negative values, and accuracy of WBC-SPECT were measured at 87%, 100%, 100%, 81%, and 92%, respectively. Addition of WBC-SPECT results to the modified Duke score helped re-classify correctly 25% of patients from possible to definite PVE. CONCLUSION: In patients with suspicion of PVE, WBC-SPECT imaging provides excellent diagnostic performance against intra-operative findings.

Impact of Systematic Whole-body 18F-Fluorodeoxyglucose PET/CT on the Management of Patients Suspected of Infective Endocarditis: The Prospective Multicenter TEPvENDO Study.

BACKGROUND: Diagnostic and patients' management modifications induced by whole-body 18F-FDG-PET/CT had not been evaluated so far in prosthetic valve (PV) or native valve (NV) infective endocarditis (IE)-suspected patients. METHODS: In sum, 140 consecutive patients in 8 tertiary care hospitals underwent 18F-FDG-PET/CT. ESC-2015-modified Duke criteria and patients' management plan were established jointly by 2 experts before 18F-FDG-PET/CT. The same experts reestablished Duke classification and patients' management plan immediately after qualitative interpretation of 18F-FDG-PET/CT. A 6-month final Duke classification was established. RESULTS: Among the 70 PV and 70 NV patients, 34 and 46 were classified as definite IE before 18F-FDG-PET/CT. Abnormal perivalvular 18F-FDG uptake was recorded in 67.2% PV and 24.3% NV patients respectively (P < .001) and extracardiac uptake in 44.3% PV and 51.4% NV patients. IE classification was modified in 24.3% and 5.7% patients (P = .005) (net reclassification index 20% and 4.3%). Patients' managements were modified in 21.4% PV and 31.4% NV patients (P = .25). It was mainly due to perivalvular uptake in PV patients and to extra-cardiac uptake in NV patients and consisted in surgery plan modifications in 7 patients, antibiotic plan modifications in 22 patients and both in 5 patients. Altogether, 18F-FDG-PET/CT modified classification and/or care in 40% of the patients (95% confidence interval: 32-48), which was most likely to occur in those with a noncontributing echocardiography (P < .001) or IE classified as possible at baseline (P = .04), while there was no difference between NV and PV. CONCLUSIONS: Systematic 18F-FDG-PET/CT did significantly and appropriately impact diagnostic classification and/or IE management in PV and NV-IE suspected patients. CLINICAL TRIALS REGISTRATION: NCT02287792.

Hypermetabolism of the spleen or bone marrow is an additional albeit indirect sign of infective endocarditis at FDG-PET.

PURPOSE: This study aimed at determining the diagnostic implications of indirect signs of infection at FDG-PET-i.e., hypermetabolisms of the spleen and/or bone marrow (HSBM)-when documented in patients with known or suspected infective endocarditis (IE). METHODS: HSBM were defined by higher mean standardized uptake values comparatively to that of the liver on FDG-PET images from patients with a high likelihood of IE and prospectively included in a multicenter study. RESULTS: Among the 129 included patients, IE was ultimately deemed as definite in 88 cases. HSBM was a predictor of definite IE (P = 0.014; odds ratio (OR) 3.2), independently of the criterion of an abnormal cardiac FDG uptake (P = 0.0007; OR 9.68), and a definite IE was documented in 97% (29/30) of patients showing both HSBM and abnormal cardiac uptake, 78% (7/9) of patients with only abnormal cardiac uptake, 67% (42/63) of patients with only HSBM, and 37% (10/27) of patients with neither one. CONCLUSION: In this cohort with a high likelihood of IE, HSBM is an additional albeit indirect sign of IE, independently of the criterion of an abnormal cardiac uptake, and could reinforce the suspicion of IE in the absence of any other infectious, inflammatory, or malignant disease.

Head-to-head comparison of the diagnostic performances of Rubidium-PET and SPECT with CZT camera for the detection of myocardial ischemia in a population of women and overweight individuals.

BACKGROUND: The aim of this study was to compare the diagnostic performances for the detection of myocardial ischemia of 82-Rb-PET-MPS and 99m-Tc-SPECT-MPS in overweight individuals and women. METHODS AND RESULTS: Men with BMI ≥ 25 and women referred for MPS were considered for inclusion. All individuals underwent 99m-Tc-SPECT-MPS with CZT cameras and 82-Rb-PET-MPS in 3D-mode. Individuals with at least one positive MPS were referred for coronary angiography (CA) with FFR measurements. A criterion for positivity was a composite endpoint including significant stenosis on CA or, in the absence of CA, the occurrence of acute coronary event during the following year. 313 patients (46% women) with mean BMI of 31.8 ± 6.5 were included. Sensitivity for the detection of myocardial ischemia was higher with 82-Rb-PET-MPS compared with 99m-Tc-SPECT-MPS (85% vs. 57%, P < .05); specificity was equally high with both imaging techniques (93% vs. 94%, P > .05). 82-Rb-PET allowed for a more accurate detection of patients with a high-risk coronary artery disease (HR-CAD) than 99m-Tc-SPECT-MPS (AUC = 0.86 vs. 0.75, respectively; P = .04). CONCLUSIONS: In women and overweight individuals, 82-Rb-PET-MPS provides higher sensitivity for the detection of myocardial ischemia than 99m-Tc-SPECT-MPS thanks to a better image quality and an improved detection of HR-CAD.

Nanostructured lipid carriers accumulate in atherosclerotic plaques of ApoE-/- mice.

Nanostructured lipid carriers (NLC) might represent an interesting approach for the identification and targeting of rupture-prone atherosclerotic plaques. In this study, we evaluated the biodistribution, targeting ability and safety of 64Cu-fonctionalized NLC in atherosclerotic mice. 64Cu-chelating-NLC (51.8±3.1 nm diameter) with low dispersity index (0.066±0.016) were produced by high pressure homogenization at tens-of-grams scale. 24 h after injection of 64Cu-chelated particles in ApoE-/- mice, focal regions of the aorta showed accumulation of particles on autoradiography that colocalized with Oil Red O lipid mapping. Signal intensity was significantly greater in aortas isolated from ApoE-/- mice compared to wild type (WT) control (8.95 [7.58, 10.16]×108 vs 4.59 [3.11, 5.03]×108 QL/mm2, P < 0.05). Moreover, NLC seemed safe in relevant biocompatibility studies. NLC could constitute an interesting platform with high clinical translation potential for targeted delivery and imaging purposes in atherosclerosis.

FDG atrial uptake is associated with an increased prevalence of stroke in patients with atrial fibrillation.

PURPOSE: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with an increased risk of stroke. Indeed, silent AF is frequently identified in unexplained ischemic stroke. 18F-FDG-PET/CT is a powerful tool for assessing myocardial metabolic shift and inflammation, both potentially at stake in AF. This case-control study investigated whether AF could promote FDG uptake in atria after physiological myocardial glucose uptake suppression, and the potential relationship between FDG atrial uptake and prevalence of stroke. METHODS: We retrospectively enrolled 128 patients (64 consecutive patients with AF and 64 without AF as the control group, matched for age and sex) who underwent 18F-FDG-PET/CT after a high-fat low-carbohydrate diet. We analyzed visual and quantitative FDG uptake parameters of the right and left atria (RA/LA) and the right and left appendages (RAA/LAA), and selected clinical features including history of stroke. RESULTS: Diffuse right atrial uptake was present in a third of patients with AF and only two patients in the control group. FDG uptake intensity of both atria was significantly associated with the underlying heart rhythm. The occurrence of stroke was strongly associated with detectable atrial uptake in multivariate analysis, with an odds ratio superior to that of other known risk factors. CONCLUSIONS: This study shows a significant correlation between FDG atrial uptake and AF. While inconsistent, this pattern seems to be associated with an increased prevalence of cardioembolic stroke.

Pharmaceutical Development and Safety Evaluation of a GMP-Grade Fucoidan for Molecular Diagnosis of Cardiovascular Diseases.

The adhesion molecule P-selectin is present on the cell surface of both activated endothelium and activated platelets. The present study describes the pharmaceutical development, safety evaluation, and preclinical efficacy of a micro-dosed radiotracer. The macromolecular nanoscale assembly consisted of a natural compound made of a sulfated fucose-rich polysaccharides (fucoidan) and a radionuclide (technetium-99m) for the detection of P-selectin expression in cardiovascular diseases. After extraction and fractionation from brown seaweeds, the good manufacturing practice (GMP) production of a low molecular weight (LMW) fucoidan of 7 kDa was achieved and full physicochemical characterization was performed. The regulatory toxicology study in rats of the GMP batch of LMW fucoidan revealed no adverse effects up to 400 µg/kg (×500 higher than the expected human dose) and pseudoallergy was not seen as well. In a myocardial ischemia-reperfusion model in rats, the GMP-grade LMW fucoidan labeled with technetium-99m detected P-selectin upregulation in vivo. The present study supports the potential of using 99mTc-fucoidan as an imaging agent to detect activated endothelium in humans.

Cardiac denervation evidenced by MIBG occurs earlier than amyloid deposits detection by diphosphonate scintigraphy in TTR mutation carriers.

PURPOSE: Cardiac involvement in familial transthyretin (TTR) amyloidosis is of major prognostic value, and the development of early-diagnostic tools that could trigger the use of new disease-modifying treatments is crucial. The aim of our study was to compare the respective contributions of 99mTc-diphosphonate scintigraphy (DPD, detecting amyloid deposits) and 123I-MIBG (MIBG, assessing cardiac sympathetic denervation) in patients with genetically proven TTR mutation referred for the assessment of cardiac involvement. METHODS: We prospectively studied 75 consecutive patients (classified as symptomatic or asymptomatic carriers), using clinical evaluation, biomarkers (troponin and BNP), echocardiography, and nuclear imaging. Patients were classified as having normal heart-to-mediastinum (HMR) MIBG uptake ratio 4 h after injection (defined by HM4 ≥ 1.85) or abnormal HM4 < 1.85, and positive DPD uptake (grade ≥ 1 of Perugini classification) or negative DPD uptake. RESULTS: Among 75 patients, 49 (65%) presented with scintigraphic sympathetic cardiac denervation and 29 (39%) with myocardial diphosphonate uptake. When MIBG was normal, DPD was negative except for two patients. Age was an independent predictor of abnormal scintigraphic result of both MIBG and DPD (HR 1.08 and 1.15 respectively), whereas echocardiographic-derived indicators of increased left ventricular filling pressure (E/e' ratio) was an independent predictor of abnormal MIBG (HR 1.33) and global longitudinal strain of positive DPD (HR 1.45). In asymptomatic patients (n = 31), MIBG was abnormal in 48% (n = 15) among whom 50% had a normal DPD; all those with a normal MIBG (n = 16) had a normal DPD. CONCLUSIONS: In TTR mutation carriers, cardiac sympathetic denervation evidenced by decreased MIBG uptake is detected earlier than amyloid burden evidenced by DPD. These results raise the possibility of a diagnostic role for MIBG scintigraphy at an early stage of cardiac involvement in TTR-mutated carriers, in addition to its well-established prognostic value.

Recommendations on nuclear and multimodality imaging in IE and CIED infections.

In the latest update of the European Society of Cardiology (ESC) guidelines for the management of infective endocarditis (IE), imaging is positioned at the centre of the diagnostic work-up so that an early and accurate diagnosis can be reached. Besides echocardiography, contrast-enhanced CT (ce-CT), radiolabelled leucocyte (white blood cell, WBC) SPECT/CT and [18F]FDG PET/CT are included as diagnostic tools in the diagnostic flow chart for IE. Following the clinical guidelines that provided a straightforward message on the role of multimodality imaging, we believe that it is highly relevant to produce specific recommendations on nuclear multimodality imaging in IE and cardiac implantable electronic device infections. In these procedural recommendations we therefore describe in detail the technical and practical aspects of WBC SPECT/CT and [18F]FDG PET/CT, including ce-CT acquisition protocols. We also discuss the advantages and limitations of each procedure, specific pitfalls when interpreting images, and the most important results from the literature, and also provide recommendations on the appropriate use of multimodality imaging.

Can Nuclear Imaging Techniques Predict Patient Outcome and Guide Medical Management in Hereditary Transthyretin Cardiac Amyloidosis?

PURPOSE OF REVIEW: Nuclear imaging recently gained a key role in the diagnosis and prognostic assessment of transthyretin (TTR)-related cardiac amyloidosis. This review aims at summarizing the state-of-the art regarding the implementation of nuclear imaging in the management of hereditary mutated TTR-cardiac amyloidosis (mTTR-CA). RECENT FINDINGS: Although cardiac uptake of bone tracers is acknowledged as a specific marker of TTR amyloid cardiac burden, recent studies validated the implementation of bone scan in the flow chart for non-invasive diagnosis and follow-up of CA in multicenter trials. Simultaneously, cardiac denervation evidenced by MIBG scintigraphy proved to be a strong and independent prognostic marker of poor outcome in mTTR-CA. By its unique ability to assess both amyloid burden and cardiac denervation, nuclear imaging may prove useful as part of multimodality imaging tools to trigger treatment initiation and monitoring in patients with mTTR-CA.

18F-FDG-PET/CT Imaging to Diagnose Septic Emboli and Mycotic Aneurysms in Patients with Endocarditis and Cardiac Device Infections.

PURPOSE OF REVIEW: This review analyzes recent studies evaluating the diagnostic value of 18F-FDG-PET/CT for the detection of peripheral emboli and secondary infectious foci in patients with infective endocarditis and cardiac device infections. RECENT FINDINGS: Detection of extracardiac septic localizations in patients with infective endocarditis and cardiac device infections is crucial, as it may impact the diagnosis, prognosis, and therapeutic management. Recent literature substantiated the clinical usefulness of 18F-FDG-PET/CT in this setting. 18F-FDG-PET/CT has proven its high diagnostic value for the detection of peripheral emboli in patients with infective endocarditis and cardiac device infections, substantially affecting patients' outcome and treatment. A multimodal approach, combining the high sensitivity of 18F-FDG-PET/CT with morphological imaging seems promising.

Nuclear imaging for patients with a suspicion of infective endocarditis: Be part of the team!

The diagnosis of infective endocarditis (IE) is challenging and requires the association of morphological features suggestive of valvular infection such as the presence of vegetations or abscesses identified usually with echocardiography and positive blood culture or serologies suggestive of systemic bacterial infection. In the past 5 years, several groups confirmed the incremental value of FDG-PET imaging and radiolabeled leukocyte scintigraphy over echocardiography for the diagnosis of IE. Based on the latter studies, the presence of abnormal activity in the perivalvular region on either FDG-PET imaging or radiolabeled leukocyte scintigraphy has been added as a major criterion for the diagnosis of IE in the guidelines recently published. Nuclear physicians should therefore learn not only the imaging criteria in favor of active IE but also the pitfalls of these nuclear imaging techniques in order to give a useful answer to the referring physician for the management of these patients. In fact, the diagnosis of IE is often complex and requires the integration of multiple clinical, biological, and imaging parameters. Multi-disciplinary teams including cardiologists, infectious disease physicians, cardiac surgeons, and radiologists have been therefore set up in several institutions to discuss the diagnosis and management of patients with a suspicion of IE. It is now time for nuclear cardiologists to join the team.