Extracellular Volume Fraction by Computed Tomography Predicts Long-Term Prognosis Among Patients With Cardiac Amyloidosis

BackgroundLight chain (AL) and transthyretin (ATTR) amyloid fibrils are deposited in the extracellular space of the myocardium, resulting in heart failure and premature mortality. Extracellular expansion can be quantified by computed tomography, offering a rapid, cheaper, and more practical alternative to cardiac magnetic resonance, especially among patients with cardiac devices or on renal dialysis.ObjectivesThis study sought to investigate the association of extracellular volume fraction by computed tomography (ECV_CT), myocardial remodeling, and mortality in patients with systemic amyloidosis.MethodsPatients with confirmed systemic amyloidosis and varying degrees of cardiac involvement underwent electrocardiography-gated cardiac computed tomography. Whole heart and septal ECV_CT was analyzed. All patients also underwent clinical assessment, electrocardiography, echocardiography, serum amyloid protein component, and/or technetium-99m (^99mTc) 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. ECV_CT was compared across different extents of cardiac infiltration (ATTR Perugini grade/AL Mayo stage) and evaluated for its association with myocardial remodeling and all-cause mortality.ResultsA total of 72 patients were studied (AL: n = 35, ATTR: n = 37; median age: 67 [IQR: 59-76] years, 70.8% male). Mean septal ECV_CT was 42.7% ± 13.1% and 55.8% ± 10.9% in AL and ATTR amyloidosis, respectively, and correlated with indexed left ventricular mass (r = 0.426; P < 0.001), left ventricular ejection fraction (r = 0.460; P < 0.001), N-terminal pro–B-type natriuretic peptide (r = 0.563; P < 0.001), and high-sensitivity troponin T (r = 0.546; P < 0.001). ECV_CT increased with cardiac amyloid involvement in both AL and ATTR amyloid. Over a mean follow-up of 5.3 ± 2.4 years, 40 deaths occurred (AL: n = 14 [35.0%]; ATTR: n = 26 [65.0%]). Septal ECV_CT was independently associated with all-cause mortality in ATTR (not AL) amyloid after adjustment for age and septal wall thickness (HR: 1.046; 95% CI: 1.003-1.090; P = 0.037).ConclusionsCardiac amyloid burden quantified by ECV_CT is associated with adverse cardiac remodeling as well as all-cause mortality among ATTR amyloid patients. ECV_CT may address the need for better identification and risk stratification of amyloid patients, using a widely accessible imaging modality.     

Diagnostic Accuracy of [11C]PIB Positron Emission Tomography for Detection of Cardiac Amyloidosis

ObjectivesThis dual-site study evaluated the diagnostic accuracy of the method.BackgroundPittsburgh compound ([¹¹C]PIB) positron emission tomography (PIB-PET) has shown promise as a specific and noninvasive method for the diagnosis of cardiac amyloidosis (CA).MethodsThe study had 2 parts. In the initial study, 51 subjects were included, 36 patients with known CA and increased wall thickness (15 immunoglobulin light chain [AL] and 21 transthyretin [ATTR] amyloidosis) and 15 control patients (7 were nonamyloid hypertrophic and 8 healthy volunteers). Subjects underwent PIB-PET and echocardiography. Sensitivity and specificity of PIB-PET were established for 2 simple semiquantitative approaches, standardized uptake value ratio (SUVR) and retention index (RI). The second part of the study included 11 amyloidosis patients (5 AL and 6 hereditary ATTR) without increased wall thickness to which the optimal cutoff values of SUVR (>1.09) and RI (>0.037 min^-1) were applied prospectively.ResultsThe diagnostic accuracy of visual inspection of [¹¹C]PIB uptake was 100% in discriminating CA patients with increased wall thickness from controls. Semiquantitative [¹¹C]PIB uptake discriminated CA from controls with a 94% (95% confidence interval [CI]: 80% to 99%) sensitivity for both SUVR and RI and specificity of 93% (95% CI: 66% to 100%) for SUVR and 100% (95% CI: 75% to 100%) for RI. [¹¹C]PIB uptake was significantly higher in AL-CA than in ATTR-CA patients (p < 0.001) and discriminated AL-CA from controls with 100% (95% CI: 88% to 100%) accuracy for both the semiquantitative measures. In the prospective group without increased wall thickness, RI was elevated compared to controls (p = 0.001) and 5 of 11 subjects were evaluated as [¹¹C]PIB PET positive.ConclusionsIn a dual-center setting, [¹¹C]PIB PET was highly accurate in detecting cardiac involvement in the main amyloid subtypes, with 100% accuracy in AL amyloidosis. A proportion of amyloidosis patients without known cardiac involvement were [¹¹C]PIB PET positive, indicating that the method may detect early stages of CA.     

Prognostic Utility of Echocardiographic Atrial and Ventricular Strain Imaging in Patients With Cardiac Amyloidosis

ObjectivesThe prognostic value of echocardiographic atrial and ventricular strain imaging in patients with biopsy-proven cardiac amyloidosis was assessed.BackgroundAlthough left ventricular global longitudinal strain (GLS) is known to be predictive of outcome, the additive prognostic value of left (LA), right atrial (RA), and right ventricular (RV) strain is unclear.MethodsOne hundred thirty-six patients with cardiac amyloidosis and available follow-up data were studied by endomyocardial biopsy, noncardiac biopsy with supportive cardiac imaging, or autopsy confirmation. One hundred nine patients (80%) had light-chain, 23 (17%) had transthyretin, and 4 (3%) had amyloid A type cardiac amyloidosis. GLS, RV free wall strain, peak longitudinal LA strain, and peak longitudinal RA strain were measured from apical views. Clinical and routine echocardiographic data were compared. All-cause mortality was followed (median 5 years).ResultsStrain data were feasible for GLS in 127 (93%), LA strain in 119 (88%), RA strain in 117 (86%), and RV strain in 102 (75%). Strain values from all 4 chambers were significantly associated with survival. Hazard ratio (HR) and 95% confidence interval (CI) for low median strain values were as follows: GLS, HR: 2.3; 95% CI: 1.3 to 3.8 (p < 0.01); LA strain, HR: 7.5; 95% CI: 3.8 to 14.7 (p < 0.001); RA strain, HR: 3.5; 95% CI: 2.0 to 6.2 (p < 0.001); and RV free wall strain, HR: 2.8; 95% CI: 1.5 to 5.1 (p < 0.001). Peak longitudinal LA strain and RV strain remained independently associated with survival in multivariable analysis. Peak LA strain had the strongest association with survival (p < 0.001), and LA strain combined with GLS and RV free wall strain had the highest prognostic value (p < 0.001).ConclusionsStrain data from all 4 chambers had important prognostic associations with survival in patients with biopsy-confirmed cardiac amyloidosis. Peak longitudinal LA strain was particularly associated with prognosis. Atrial and ventricular strain have promise for clinical utility.     

Diagnostic Accuracy of Cardiac Computed Tomography and 18-F Fluorodeoxyglucose Positron Emission Tomography in Cardiac Masses

ObjectivesThis study sought to assess the diagnostic accuracy of cardiac computed tomography (CT) and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) with positron emission tomography/computed tomography (PET/CT) in defining the nature of cardiac masses.BackgroundThe diagnostic accuracy of cardiac CT and ¹⁸F-FDG PET/CT in identifying the nature of cardiac masses has been analyzed to date only in small samples.MethodsOf 223 patients with echocardiographically diagnosed cardiac masses, a cohort of 60 cases who underwent cardiac CT and ¹⁸F-FDG PET/CT was selected. All masses had histological confirmation, except for a minority of thrombotic formations. For each mass, 8 morphological CT signs, standardized uptake value (SUV_max, SUV_mean), metabolic tumor volume, and total lesion glycolysis in ¹⁸F-FDG PET were used as diagnostic markers.ResultsIrregular tumor margins, pericardial effusion, invasion, solid nature, mass diameter, CT contrast uptake, and pre-contrast characteristics were strongly associated with the malignant nature of masses. The coexistence of at least 5 CT signs perfectly identified malignant masses, whereas the detection of 3 or 4 CT signs did not accurately discriminate the masses’ nature. The mean SUV_max, SUV_mean, metabolic tumor volume, and total lesion glycolysis values were significantly higher in malignant than in benign masses. The diagnostic accuracy of SUV, metabolic tumor volume, and total lesion glycolysis ¹⁸F-FDG PET/CT parameters was excellent in detecting malignant masses. Among patients with 3 or 4 pathological CT signs, the presence of at least 1 abnormal ¹⁸F-FDG PET/CT parameter significantly increased the identification of malignancies.ConclusionsCardiac CT is a powerful tool to diagnose cardiac masses as the number of abnormal signs was found to correlate with the lesions’ nature. Similarly, ¹⁸F-FDG PET/CT accurately identified malignant masses and contributed with additional valuable information in diagnostic uncertainties after cardiac CT. These imaging tools should be performed in specific clinical settings such as involvement of great vessels or for disease-staging purposes.     

Unveiling Cardiac Amyloidosis,its Characteristics,and Outcomes Among Patients With MR Undergoing Transcatheter Edge-to-Edge MV Repair

BackgroundMitral regurgitation (MR) and cardiac amyloidosis (CA) both primarily affect older patients. Data on coexistence and prognostic implications of MR and CA are currently lacking.ObjectivesThis study sought to identify the prevalence, clinical characteristics, and outcomes of MR CA compared with lone MR.MethodsConsecutive patients undergoing transcatheter edge-to-edge repair (TEER) for MR at 2 sites were screened for concomitant CA using a multiparametric approach including core laboratory ^99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid bone scintigraphy and echocardiography and immunoglobulin light chain assessment. Transthyretin CA (ATTR) was diagnosed by ^99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (Perugini grade 1: early infiltration; grades 2/3: clinical CA) and the absence of monoclonal protein, and light chain (AL) CA via tissue biopsy. All-cause mortality and hospitalization for heart failure (HHF) served as the endpoints.ResultsA total of 120 patients (age 76.9 ± 8.1 years, 55.8% male) were recruited. Clinical CA was diagnosed in 14 patients (11.7%; 12 ATTR, 1 AL, and 1 combined ATTR/AL) and early amyloid infiltration in 9 patients (7.5%). Independent predictors of MR CA were increased posterior wall thickness and the presence of a left anterior fascicular block on electrocardiography. Procedural success and periprocedural complications of TEER were similar in MR CA and lone MR (P for all = NS). After a median of 1.7 years, 25.8% had experienced death and/or HHF. MR CA had worse outcomes compared with lone MR (HR: 2.2; 95% CI: 1.0-4.7; P = 0.034), driven by a 2.5-fold higher risk for HHF (HR: 2.5; 95% CI: 1.1-5.9), but comparable mortality (HR: 1.6; 95% CI: 0.4-6.1).ConclusionsDual pathology of MR CA is common in elderly patients with MR undergoing TEER and has worse postinterventional outcomes compared with lone MR.     

Velocities of Naturally Occurring Myocardial Shear Waves Increase With Age and in Cardiac Amyloidosis

ObjectivesThis study sought to evaluate whether velocity of naturally occurring myocardial shear waves (SW) could relate to myocardial stiffness (MS) in vivo.BackgroundCardiac SW imaging has been proposed as a noninvasive tool to assess MS. SWs occur after mechanical excitation of the myocardium (e.g., mitral valve closure [MVC] and aortic valve closure [AVC]), and their propagation velocity is theoretically related to MS, thus providing an opportunity to assess stiffness at end-diastole (ED) and end-systole. However, given that SW propagation in vivo is complex, it remains unclear whether natural SW velocity effectively relates to MS.MethodsThis study prospectively enrolled 50 healthy volunteers (HV) (43.7 ± 17.1 years of age) and 18 patients with cardiac amyloidosis (CA) (68.0 ± 9.8 years of age). HV were divided into 3 age groups: group I, 20 to 39 years of age (n = 24); group II, 40 to 59 years of age (n = 11); and group III, 60 to 80 years of age (n = 15). Parasternal long-axis views were acquired using an experimental scanner. Tissue (Doppler) acceleration maps were extracted from an anatomical M-mode along the midline of the left ventricular septum.ResultsSW propagation velocity was significantly higher in CA patients than in HV after both MVC (3.54 ± 0.93 m/s vs. 6.33 ± 1.63 m/s, respectively; p < 0.001) and AVC (3.75 ± 0.76 m/s vs. 5.63 ± 1.13 m/s, respectively; p < 0.001). Similarly, SW propagation velocity differed significantly among age groups in HV, with a significantly higher value for group III than for group I, both occurring after MVC (p < 0.001) and AVC (p < 0.01). Moreover, SW propagation velocity after MVC was found to be significantly higher in patients with an increasing grade of diastolic dysfunction (p < 0.001). Finally, positive correlation was found between SW velocities after MVC and mitral inflow-to-mitral relaxation velocity ratio (E/E′) (r = 0.74; p = 0.002).ConclusionsEnd-diastole SW velocities were significantly higher in patients with CA, patients with a higher grade of diastolic dysfunction, and elderly volunteers. These findings thus suggest that the speed of naturally induced SWs may be related to MS.     

Hybrid Cardiac Magnetic Resonance/Fluorodeoxyglucose Positron Emission Tomography to Differentiate Active From Chronic Cardiac Sarcoidosis

ObjectivesThe purpose of this study was to investigate the diagnostic value of simultaneous hybrid cardiac magnetic resonance (CMR) and ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) for detection and differentiation of active (aCS) from chronic (cCS) cardiac sarcoidosis.BackgroundLate gadolinium enhancement (LGE) CMR and FDG-PET are both established imaging techniques for the detection of CS. However, there are limited data regarding the value of a comprehensive simultaneous hybrid CMR/FDG-PET imaging approach that includes CMR mapping techniques.MethodsForty-three patients with biopsy-proven extracardiac sarcoidosis (median age: 48 years, interquartile range: 37-57 years, 65% male) were prospectively enrolled for evaluation of suspected CS. After dietary preparation for suppression of myocardial glucose metabolism, patients were evaluated on a 3-T hybrid PET/MR scanner. The CMR protocol included T1 and T2 mapping, myocardial function, and LGE imaging. We assumed aCS if PET and CMR (ie, LGE or T1/T2 mapping) were both positive (PET+/CMR+), cCS if PET was negative but CMR was positive (PET?/CMR+), and no CS if patients were CMR negative regardless of PET findings.ResultsAmong the 43 patients, myocardial glucose uptake was suppressed successfully in 36 (84%). Hybrid CMR/FDG-PET revealed aCS in 13 patients (36%), cCS in 5 (14%), and no CS in 18 (50%). LGE was present in 14 patients (39%); T1 mapping was abnormal in 10 (27%) and T2 mapping abnormal in 2 (6%). CS was diagnosed based on abnormal T1 mapping in 4 out of 18 CS patients (22%) who were LGE negative. PET FDG uptake was present in 17 (47%) patients.ConclusionsComprehensive simultaneous hybrid CMR/FDG-PET imaging is useful for the detection of CS and provides additional value for identifying active disease. Our results may have implications for enhanced diagnosis as well as improved identification of patients with aCS in whom anti-inflammatory therapy may be most beneficial.     

Clinical Importance of Left Atrial Infiltration in Cardiac Transthyretin Amyloidosis

ObjectivesThe aim of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in a large cohort of patients with ATTR-CM; and to study the association with mortality.BackgroundThe clinical significance of LA involvement in ATTR-CM is of great clinical interest.MethodsCongo red staining and immunohistochemistry was performed to assess the presence, type, and extent of amyloid and associated changes in 5 explanted ATTR-CM atria. Echo speckle tracking was used to assess LA reservoir, conduit, contractile function, and stiffness in 906 patients with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other).ResultsThere was extensive ATTR amyloid infiltration in the 5 atria, with loss of normal architecture, vessels remodeling, capillary disruption, and subendocardial fibrosis. Echo speckle tracking in 906 patients with ATTR-CM demonstrated increased atrial stiffness (median [25th-75th quartile] 1.83 [1.15-2.92]) that remained independently associated with prognosis after adjusting for known predictors (lnLA stiff: HR: 1.23; 95% CI: 1.03-1.49; P = 0.029). There was substantial impairment of the 3 phasic functional atrial components (reservoir 8.86% [5.94%-12.97%]; conduit 6.5% [4.53%-9.28%]; contraction function 4.0% [2.29%-6.56%]). Atrial contraction was absent in 22.1% of patients whose electrocardiograms showed sinus rhythm (SR) “atrial electromechanical dissociation” (AEMD). AEMD was associated with poorer prognosis compared with patients with SR and effective mechanical contraction (P = 0.0018). AEMD conferred a similar prognosis to patients in atrial fibrillation.ConclusionsThe phenotype of ATTR-CM includes significant infiltration of the atrial walls, with progressive loss of atrial function and increased stiffness, which is a strong independent predictor of mortality. AEMD emerged as a distinctive phenotype identifying patients in SR with poor prognosis.     

Pre-Treatment Myocardial 18FDG Uptake Predicts Response to Immunosuppression in Patients With Cardiac Sarcoidosis

ObjectivesThis study identified predictors of clinical (CR) and echocardiographic response (ER) following immunosuppressive therapy (IST) in patients with cardiac sarcoidosis (CS).BackgroundIST has been the cornerstone of treatment for patients with CS and active myocardial inflammation. However, there are little data to explain the variable response to IST in CS.MethodsData of 96 consecutive patients with CS from the Granulomatous Myocarditis Registry were analyzed. All patients underwent a ¹⁸fluorodeoxy glucose positron emission tomography−computed tomography (¹⁸FDG-PET-CT) before initiation of IST. Response was assessed after 4 to 6 months of therapy. CR was defined as an improvement in functional class (New York Heart Association functional class ≥I) and freedom from ventricular arrhythmias and heart failure hospitalizations. ER was defined as an improvement in left ventricular ejection fraction (LVEF) ≥10%. ER was assessed only in patients with a LVEF <50%. Complete responders had no residual myocardial FDG uptake and fulfilled both response criteria. Partial responders fulfilled only 1 response criteria or had residual FDG uptake. Nonresponders did not fulfill either CR or ER criteria. The uptake index (UI) was defined as the product of maximum standardized uptake value and the number of LV segments with abnormal uptake on ¹⁸FDG-PET-CT.ResultsAmong 91 patients included in the final analysis, 54.9%, 20.9%, and 24.2% of patients were classified as complete and partial responders and nonresponders, respectively. Cox regression analysis (all responders vs. nonresponders) identified the following as independent predictors of response following immunosuppression: LVEF >40% (hazard ratio: 1.61; 95% confidence interval: 1.06 to 7.69; p = 0.031) and myocardial UI >30 (hazard ratio: 1.28; 95% confidence interval: 1.05 to 6.12; p = 0.010). The final model had a good discriminative power (area under the curve [AUC]: 0.85) and predictive accuracy (sensitivity: 85.5%; specificity: 86.4%). Pre-treatment myocardial UI had a strong positive correlation with change in LVEF following immunosuppression.ConclusionsPre-treatment ¹⁸FDG myocardial uptake was a predictor of CR and ER response to immunosuppression in patients with CS.     

Multi-Imaging Characterization of Cardiac Phenotype in Different Types of Amyloidosis

BackgroundBone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of different degrees of cardiac uptake across different types is yet to be defined.ObjectivesThis study sought to define the phenotypes of patients with varying degrees of cardiac uptake on bone scintigraphy, across multiple types of systemic amyloidosis, using extensive characterization comprising biomarkers as well as echocardiographic and cardiac magnetic resonance (CMR) imaging.MethodsA total of 296 patients (117 with immunoglobulin light-chain amyloidosis [AL], 165 with transthyretin amyloidosis [ATTR], 7 with apolipoprotein AI amyloidosis [AApoAI], and 7 with apolipoprotein AIV amyloidosis [AApoAIV]) underwent deep characterization of their cardiac phenotype.ResultsAL patients with grade 0 myocardial radiotracer uptake spanned the spectrum of CMR findings from no CA to characteristic CA, whereas AL patients with grades 1 to 3 always produced characteristic CMR features. In ATTR, the CA burden strongly correlated with myocardial tracer uptake, except in Ser77Tyr. AApoAI presented with grade 0 or 1 and disproportionate right-sided involvement. AApoAIV always presented with grade 0 and characteristic CA. AL grade 1 patients (n = 48; 100%) had characteristic CA, whereas only ATTR grade 1 patients with Ser77Tyr had characteristic CA on CMR (n = 5; 11.4%). After exclusion of Ser77Tyr, AApoAI, and AApoAIV, CMR showing characteristic CA or an extracellular volume of >0.40 in patients with grade 0 to 1 cardiac uptake had a sensitivity and specificity of 100% for AL.ConclusionsThere is a wide variation in cardiac phenotype between different amyloidosis types across different degrees of cardiac uptake. The combination of CMR and bone scintigraphy can help to define the diagnostic differentials and the clinical phenotype in each individual patient.     

Cardiac Radiation Dose,Cardiac Disease,and Mortality in Patients With Lung Cancer

BackgroundRadiotherapy-associated cardiac toxicity studies in patients with locally advanced non–small cell lung cancer (NSCLC) have been limited by small sample size and nonvalidated cardiac endpoints.ObjectivesThe purpose of this analysis was to ascertain whether cardiac radiation dose is a predictor of major adverse cardiac events (MACE) and all-cause mortality (ACM).MethodsThis retrospective analysis included 748 consecutive locally advanced NSCLC patients treated with thoracic radiotherapy. Fine and Gray and Cox regressions were used to identify predictors for MACE and ACM, adjusting for lung cancer and cardiovascular prognostic factors, including pre-existing coronary heart disease (CHD).ResultsAfter a median follow-up of 20.4 months, 77 patients developed ≥1 MACE (2-year cumulative incidence, 5.8%; 95% confidence interval [CI]: 4.3% to 7.7%), and 533 died. Mean radiation dose delivered to the heart (mean heart dose) was associated with a significantly increased risk of MACE (adjusted hazard ratio [HR]: 1.05/Gy; 95% CI: 1.02 to 1.08/Gy; p < 0.001) and ACM (adjusted HR: 1.02/Gy; 95% CI: 1.00 to 1.03/Gy; p = 0.007). Mean heart dose (≥10 Gy vs. <10 Gy) was associated with a significantly increased risk of ACM in CHD-negative patients (178 vs. 118 deaths; HR: 1.34; 95% CI: 1.06 to 1.69; p = 0.014) with 2-year estimates of 52.2% (95% CI: 46.1% to 58.5%) versus 40.0% (95% CI: 33.5% to 47.4%); but not among CHD-positive patients (112 vs. 82 deaths; HR: 0.94; 95% CI: 0.70 to 1.25; p = 0.66) with 2-year estimates of 54.6% (95% CI: 46.8% to 62.7%) versus 50.8% (95% CI: 41.5% to 60.9%), respectively (p for interaction = 0.028).ConclusionsDespite the competing risk of cancer-specific death in locally advanced NSCLC patients, cardiac radiation dose exposure is a modifiable cardiac risk factor for MACE and ACM, supporting the need for early recognition and treatment of cardiovascular events and more stringent avoidance of high cardiac radiotherapy dose.     

Dynamic Stress Computed Tomography Perfusion With a Whole-Heart Coverage Scanner in Addition to Coronary Computed Tomography Angiography and Fractional Flow Reserve Computed Tomography Derived

ObjectivesThe aims of the study were to test the diagnostic accuracy of integrated evaluation of dynamic myocardial computed tomography perfusion (CTP) on top of coronary computed tomography angiography (cCTA) plus fractional flow reserve computed tomography derived (FFR_CT) by using a whole-heart coverage computed tomography (CT) scanner as compared with clinically indicated invasive coronary angiography (ICA) and invasive fractional flow reserve (FFR).BackgroundRecently, new techniques such as dynamic stress computed tomography perfusion (stress-CTP) emerged as potential strategies to combine anatomical and functional evaluation in a one-shot scan. However, previous experiences with this technique were associated with high radiation exposure.MethodsEighty-five consecutive symptomatic patients scheduled for ICA were prospectively enrolled. All patients underwent rest cCTA followed by stress dynamic CTP with a whole-heart coverage CT scanner (Revolution CT, GE Healthcare, Milwaukee, Wisconsin). FFR_CT was also measured by using the rest cCTA dataset. The diagnostic accuracy to detect functionally significant coronary artery disease (CAD) in a vessel-based model of cCTA alone, cCTA+FFR_CT, cCTA+CTP, or cCTA+FFR_CT+CTP were assessed and compared by using ICA and invasive FFR as reference. The overall effective dose of dynamic CTP was also measured.ResultsThe prevalence of obstructive CAD and functionally significant CAD was 77% and 57%, respectively. The sensitivity and specificity of cCTA alone, cCTA+FFR_CT, and cCTA+CTP were 83% and 66%, 86% and 75%, and 73% and 86%, respectively. Both the addition of FFR_CT and CTP improves the area under the curve (AUC: 0.876 and 0.878, respectively) as compared with cCTA alone (0.826; p < 0.05). The sequential strategy of cCTA+FFR_CT+CTP showed the highest AUC (0.919; p < 0.05) as compared with all other strategies. The mean effective radiation dose (ED) for cCTA and stress CTP was 2.8 ± 1.2 mSv and 5.3 ± 0.7 mSv, respectively.ConclusionsThe addition of dynamic stress CTP on top of cCTA and FFR_CT provides additional diagnostic accuracy with acceptable radiation exposure.     

Pre-Hospital Administration of Epinephrine in Pediatric Patients With Out-of-Hospital Cardiac Arrest

BackgroundThere is little evidence about pre-hospital advanced life support including epinephrine administration for pediatric out-of-hospital cardiac arrests (OHCAs).ObjectivesThis study aimed to assess the effect of pre-hospital epinephrine administration by emergency-medical-service (EMS) personnel for pediatric OHCA.MethodsThis nationwide population-based observational study in Japan enrolled pediatric patients age 8 to 17 years with OHCA between January 2007 and December 2016. Patients were sequentially matched with or without epinephrine during cardiac arrest using a risk-set matching based on time-dependent propensity score (probability of receiving epinephrine) calculated at each minute after initiation of cardiopulmonary resuscitation by EMS personnel. The primary endpoint was 1-month survival. Secondary endpoints were 1-month survival with favorable neurological outcome, defined as the cerebral performance category scale of 1 or 2, and pre-hospital return of spontaneous circulation (ROSC).ResultsDuring the study period, a total of 1,214,658 OHCA patients were registered, and 3,961 pediatric OHCAs were eligible for analyses. Of these, 306 (7.7%) patients received epinephrine and 3,655 (92.3%) did not receive epinephrine. After time-dependent propensity score-sequential matching, 608 patients were included in the matched cohort. In the matched cohort, there were no significant differences between the epinephrine and no epinephrine groups in 1-month survival (epinephrine: 10.2% [31 of 304] vs. no epinephrine: 7.9% [24 of 304]; risk ratio [RR]: 1.13 [95% confidence interval (CI): 0.67 to 1.93]) and favorable neurological outcome (epinephrine: 3.6% [11 of 304] vs. no epinephrine: 2.6% [8 of 304]; RR: 1.56 [95% CI: 0.61 to 3.96]), whereas the epinephrine group had a higher likelihood of achieving pre-hospital ROSC (epinephrine: 11.2% [34 of 304] vs. no epinephrine: 3.3% [10 of 304]; RR: 3.17 [95% CI: 1.54 to 6.54]).ConclusionsIn this study, pre-hospital epinephrine administration was associated with ROSC, whereas there were no significant differences in 1-month survival and favorable neurological outcome between those with and without epinephrine.     

Deep Learning on Bone Scintigraphy to Detect Abnormal Cardiac Uptake at Risk of Cardiac Amyloidosis

BackgroundCardiac uptake on technetium-99m whole-body scintigraphy (WBS) is almost pathognomonic of transthyretin cardiac amyloidosis. The rare false positives are often related to light-chain cardiac amyloidosis. However, this scintigraphic feature remains largely unknown, leading to misdiagnosis despite characteristic images. A retrospective review of all WBSs in a hospital database to detect those with cardiac uptake may allow the identification of undiagnosed patients.ObjectivesThe authors sought to develop and validate a deep learning–based model that automatically detects significant cardiac uptake (Perugini grade ≥2) on WBS from large hospital databases in order to retrieve patients at risk of cardiac amyloidosis.MethodsThe model is based on a convolutional neural network with image-level labels. The performance evaluation was performed with C-statistics using a 5-fold cross-validation scheme stratified so that the proportion of positive and negative WBSs remained constant across folds and using an external validation data set.ResultsThe training data set consisted of 3,048 images: 281 positives (Perugini grade ≥2) and 2,767 negatives. The external validation data set consisted of 1,633 images: 102 positives and 1,531 negatives. The performance of the 5-fold cross-validation and external validation was as follows: 98.9% (± 1.0) and 96.1% for sensitivity, 99.5% (± 0.4) and 99.5% for specificity, and 0.999 (SD = 0.000) and 0.999 for the area under the curve of the receiver-operating characteristic curves. Sex, age <90 years, body mass index, injection-acquisition delay, radionuclides, and the indication of WBS only slightly affected performances.ConclusionsThe authors’ detection model is effective at identifying patients with cardiac uptake Perugini grade ≥2 on WBS and may help in the diagnosis of patients with cardiac amyloidosis.     

Prognostic Value of RV Abnormalities on CMR in Patients With Known or Suspected Cardiac Sarcoidosis

BackgroundLeft ventricular abnormalities in cardiac sarcoidosis (CS) are associated with adverse cardiovascular events, whereas the prognostic value of right ventricular (RV) involvement found on cardiac magnetic resonance is unclear.ObjectivesThis study aimed to systematically assess the prognostic value of right ventricular ejection fraction (RVEF) and RV late gadolinium enhancement (LGE) in known or suspected CS.MethodsThis study was prospectively registered in PROSPERO (CRD42022302579). PubMed, Embase, and Web of Science were searched to identify studies that evaluated the association between RVEF or RV LGE on clinical outcomes in CS. A composite endpoint of all-cause death, cardiovascular events, or sudden cardiac death (SCD) was used. A meta-analysis was performed to determine the pooled risk ratio (RR) for these adverse events. The calculated sensitivity, specificity, and area under the curve with 95% CIs were weighted and summarized.ResultsEight studies including a total of 899 patients with a mean follow-up duration of 3.2 ± 0.7 years were included. The pooled RR of RV systolic dysfunction was 3.1 (95% CI: 1.7-5.5; P < 0.01) for composite events and 3.0 (95% CI: 1.3-7.0; P < 0.01) for SCD events. In addition, CS patients with RV LGE had a significant risk for composite events (RR: 4.8 [95% CI: 2.4-9.6]; P < 0.01) and a higher risk for SCD (RR: 9.5 [95% CI: 4.4-20.5]; P < 0.01) than patients without RV LGE. Furthermore, the pooled area under the curve, sensitivity, and specificity of RV LGE for identifying patients with CS who were at highest SCD risk were 0.8 (95% CI: 0.8-0.9), 69% (95% CI: 50%-84%), and 90% (95% CI: 70%-97%), respectively.ConclusionsIn patients with known or suspected CS, RVEF and RV LGE were both associated with adverse events. Furthermore, RV LGE shows good discrimination in identifying CS patients at high risk of SCD.     

Managing Patients With Moderate Aortic Stenosis

Current guidelines recommend that clinical surveillance for patients with moderate aortic stenosis (AS) and aortic valve replacement (AVR) may be considered if there is an indication for coronary revascularization. Recent observational studies, however, have shown that moderate AS is associated with an increased risk of cardiovascular events and mortality. Whether the increased risk of adverse events is caused by associated comorbidities, or to the underlying moderate AS itself, is incompletely understood. Similarly, which patients with moderate AS need close follow-up or could potentially benefit from early AVR is also unknown. In this review, the authors provide a comprehensive overview of the current published reports on moderate AS. They first provide an algorithm that helps to diagnose moderate AS correctly, especially when discordant grading is observed. Although the traditional focus of AS assessment has been on the valve, it is increasingly acknowledged that AS is not only a disease of the aortic valve but also of the ventricle. The authors therefore discuss how multimodality imaging can help to evaluate the left ventricular remodeling response and improve risk stratification in patients with moderate AS. Finally, they summarize current evidence on the management of moderate AS and highlight ongoing trials on AVR in moderate AS.     

Prognostic Value of Right Ventricular Function in Patients With Suspected Myocarditis Undergoing Cardiac Magnetic Resonance

BackgroundRisk-stratification of myocarditis is based on functional parameters and tissue characterization of the left ventricle (LV), whereas right ventricular (RV) involvement remains mostly unrecognized.ObjectivesIn this study, the authors sought to analyze the prognostic value of RV involvement in myocarditis by cardiac magnetic resonance (CMR).MethodsPatients meeting the recommended clinical criteria for suspected myocarditis were enrolled at 2 centers. Exclusion criteria were the evidence of coronary artery disease, pulmonary artery hypertension or structural cardiomyopathy. Biventricular ejection fraction, edema according to T2-weighted images, and late gadolinium enhancement (LGE) were linked to a composite end point of major adverse cardiovascular events (MACE), including heart failure hospitalization, ventricular arrhythmia, recurrent myocarditis, and death.ResultsAmong 1,125 consecutive patients, 736 (mean age: 47.8 ± 16.1 years) met the clinical diagnosis of suspected myocarditis and were followed for 3.7 years. Signs of RV involvement (abnormal right ventricular ejection fraction [RVEF], RV edema, and RV-LGE) were present in 188 (25.6%), 158 (21.5%), and 92 (12.5%) patients, respectively. MACE occurred in 122 patients (16.6%) and was univariably associated with left ventricular ejection fraction (LVEF), LV edema, LV-LGE, RV-LGE, RV edema, and RVEF. In a series of nesting multivariable Cox regression models, the addition of RVEF (HR_adj: 0.974 [95% CI: 0.956-0.993]; P = 0.006) improved prognostication (chi-square test = 89.5; P = 0.001 vs model 1; P = 0.006 vs model 2) compared with model 1 including only clinical variables (chi-square test = 28.54) and model 2 based on clinical parameters, LVEF, and LV-LGE extent (chi-square test = 78.93).ConclusionsThis study emphasizes the role of RV involvement in myocarditis and demonstrates the independent and incremental prognostic value of RVEF beyond clinical variables, CMR tissue characterization, and LV function. (Inflammatory Cardiomyopathy Bern Registry [FlamBER]; NCT04774549; CMR Features in Patients With Suspected Myocarditis [CMRMyo]; NCT03470571)     

Prognostic Significance of Cardiac 123I-MIBG SPECT Imaging in Heart Failure Patients With Preserved Ejection Fraction

ObjectivesThe authors sought to elucidate the prognostic value of cardiac sympathetic nerve dysfunction as evaluated using iodine-123-labeled metaiodobenzylguanidine (¹²³I-MIBG) single-photon emission computed tomography (SPECT) imaging in patients with heart failure (HF) with preserved left ventricular ejection fraction (HFpEF).BackgroundCardiac sympathetic nerve dysfunction assessed by ¹²³I-MIBG imaging is associated with poor outcomes in chronic HF patients with reduced left ventricular ejection fraction (HFrEF). However, no information is available on the prognostic vale of cardiac ¹²³I-MIBG SPECT imaging in patients with HFpEF.MethodsWe studied 148 patients admitted for acute decompensated HF (ADHF) with nonischemic HFpEF and who underwent cardiac ¹²³I-MIBG imaging at discharge. The cardiac ¹²³I-MIBG heart-to-mediastinum ratio (H/M) was measured on the delayed planar image (late H/M). SPECT analysis of the delayed image was conducted, and the tracer uptake in all 17 regions on the polar map was scored on a 5-point scale by comparison with a sex-matched normal control database. The total defect score (TDS) was calculated by summing the score of each of the 17 segments. The primary endpoint was the association between TDS and cardiac events (the composite of emergent HF hospitalization and cardiac death).ResultsDuring a mean follow-up period of 2.4 ± 1.6 years, 61 patients experienced cardiac events. TDS was significantly associated with cardiac events after multivariate Cox adjustment (P < 0.0001). Patients with high TDS levels had a significantly greater risk of cardiac events than those with middle or low TDS levels (63% vs 40% vs 20%, respectively; P < 0.0001; HR: 4.69; 95% CI: 2.29 to 9.61; and HR: 2.46; 95% CI: 1.14 to 5.29). C-statistic of TDS was 0.730 (95% CI: 0.651 to 0.799), which was significantly higher than that of late H/M (0.607; 95% CI: 0.524 to 0.686; P = 0.0228).ConclusionsCardiac ¹²³I-MIBG SPECT imaging provided useful prognostic information in nonischemic ADHF patients with HFpEF. (Clinical Trial: Osaka Prefectural Acute Heart Failure Syndrome Registry [OPAR]: UMIN000015246)     

Prognostic Value of Computed Tomography–Derived Extracellular Volume in TAVR Patients With Low-Flow Low-Gradient Aortic Stenosis

ObjectivesThe association between extracellular volume (ECV) measured by computed tomography angiography (CTA) and clinical outcomes was evaluated in low-flow low-gradient (LFLG) aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR).BackgroundPatients with LFLG AS comprise a high-risk group with respect to clinical outcomes. Although ECV, a marker of myocardial fibrosis, is traditionally measured with cardiac magnetic resonance, it can also be measured using cardiac CTA. The authors hypothesized that in LFLG AS, increased ECV may be associated with adverse clinical outcomes.MethodsIn 150 LFLG patients with AS who underwent TAVR, ECV was quantified using pre-TAVR CTA. Echocardiographic and clinical information including all-cause death and heart failure rehospitalization (HFH) was obtained from electronic medical records. A Cox proportional hazards model was used to evaluate the association between ECV and death+HFH.ResultsDuring a median follow-up of 13.9 months (range 0.07 to 28.9 months), there were 31 death+HFH events (21%). Patients who experienced death+HFH had a greater median Society of Thoracic Surgery score (9.9 vs. 4.7; p < 0.01), lower left ventricular ejection fraction (42.3 ± 20.2% vs. 52.7 ± 17.2%; p < 0.01), lower mean transvalvular gradient (24.9 ± 8.9 mm Hg vs. 28.1 ± 7.3 mm Hg; p = 0.04) and increased mean ECV (35.5 ± 9.6% vs. 29.9 ± 8.2%; p < 0.01) compared with patients who did not experience death+HFH. In a multivariable Cox proportional hazards model, increase in ECV was associated with increase in death+HFH, (hazard ratio per 1% increase: 1.04, 95% confidence interval: 1.01 to 1.09; p < 0.01).ConclusionsIn patients with LFLG AS, CTA measured increase in ECV is associated with increased risk of adverse clinical outcomes post-TAVR and may thus serve as a useful noninvasive marker for prognostication.