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  • Clinical Outcomes of Dynamic Computed Tomography Myocardial Perfusion Imaging Combined With Coronary Computed Tomography Angiography Versus Coronary Computed Tomography Angiography–Guided Strategy
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2020-01-08
    Mengmeng Yu; Chengxing Shen; Xu Dai; Zhigang Lu; Yining Wang; Bin Lu; Jiayin Zhang

    Background:Dynamic computed tomography (CT) myocardial perfusion imaging (MPI) provides quantitative myocardial blood flow for the precise assessment of myocardial ischemia. However, compared with coronary CT angiography (CCTA), whether this functional imaging modality can reduce invasive coronary angiography without revascularization remains unknown. We aimed to determine the clinical outcomes of a dynamic CT-MPI+CCTA-guided versus CCTA-guided strategy in patients with suspected coronary artery disease.Methods:Consecutive patients with intermediate pretest probability of coronary artery disease were prospectively enrolled and randomized to dynamic CT-MPI+CCTA-guided or CCTA-guided workup. The primary end point was the rate of invasive coronary angiography without revascularization within 3 months. The secondary end point was a composite of major adverse cardiac event at the 3-month, 6-month, and 1-year follow-up.Results:A total of 240 patients (mean age, 69.01±11.2 years; 173 men) were included. The total radiation dose and contrast media usage within 90 days were higher in the CT-MPI+CCTA group than in the CCTA group (10.3 versus 7.1 mSv, P=0.031; 134.5±40.6 versus 108.1±48.2 mL, P<0.0001). Compared with the CCTA-guided group, the CT-MPI+CCTA-guided group had significantly lower rates of invasive coronary angiography within 90 days (48.3% [58/120] versus 30.8% [37/120], P=0.006) and invasive coronary angiography without revascularization (50.0% [29/58] versus 10.8% [4/37], P<0.0001). There were no significant differences regarding the frequency of major adverse cardiac event between the 2 groups at the 3-month, 6-month, and 1-year follow-up.Conclusions:In patients with intermediate pretest probability of coronary artery disease, CT-MPI+CCTA-guided patient management may be preferred over the CCTA-guided strategy as an approach to reduce unnecessary invasive procedures.

  • Vascular Landmark-Based Method for Highly Reproducible Measurement of Left Atrial Appendage Volume in Computed Tomography
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-12-17
    Andrew Schluchter; Chelsea Jan; Katherine Lowe; Davis M. Vigneault; Francisco Contijoch; Elliot R. McVeigh

    Background:Modern computed tomographic scanning can produce 4-dimensional images of the left atrial appendage (LAA). LAA function and morphology can then be measured, to plan interventions such as occlusion and to evaluate LAA flow for thrombogenic risk analysis. A current problem here is defining a reproducible boundary between the LAA and the left atrium.Methods:This study used retrospectively gated 4-dimensional computed tomographic data from 25 implantation and coronary artery imaging patients. In each patient, the LAA ostium was defined at multiple time points during the RR interval. To examine the reproducibility of the definition of the LAA ostium, 3 observers analyzed all time frames in each patient 3 times. Five nonconsecutive time frames from each patient were then compared using intraclass correlation coefficients to quantify the precision of the method across patients. The correlation of LAA volumes for each time frame of each patient was determined across the different observers (interobserver) and within each observer’s own data sets (intraobserver).Results:The method was successful in 92% of patients. Two-way random-effect, absolute-agreement, single-measurement intraclass correlation coefficients for interobserver measurements were 0.984, 0.990, and 0.988, with intraobserver intraclass correlation coefficients of 0.989, 0.989, and 0.995. The intraclass correlation coefficient of all observations was 0.988.Conclusions:Classification of the LAA ostium using a stepwise procedure identifying the coumadin ridge and 2 vascular landmarks in ECG-gated computed tomography provides a viable method of establishing a highly reproducible boundary between the atrium and LAA needed to obtain LAA metrics useful for procedure planning and measuring LAA function.

  • Myocardial Extracellular Volume Fraction Adds Prognostic Information Beyond Myocardial Replacement Fibrosis
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-12-16
    Eric Y. Yang; Mohamad G. Ghosn; Mohammad A. Khan; Nickalaus L. Gramze; Gerd Brunner; Faisal Nabi; Vijay Nambi; Sherif F. Nagueh; Duc T. Nguyen; Edward A. Graviss; Erik B. Schelbert; Christie M. Ballantyne; William A. Zoghbi; Dipan J. Shah

    Background:Cardiac magnetic resonance techniques permit quantification of the myocardial extracellular volume fraction (ECV), representing a surrogate marker of reactive interstitial fibrosis, and late gadolinium enhancement (LGE), representing replacement fibrosis or scar. ECV and LGE have been independently linked with heart failure (HF) events. In deriving ECV, coronary artery disease type LGE, but not non-coronary artery disease type LGE, has been consistently excluded. We examined the associations between LGE, global ECV derived from myocardial tissue segments free of any detectable scar, and subsequent HF events.Methods:Mid short-axis T1 maps were divided into 6 cardiac segments, each classified as LGE absent or present. Global ECV was derived from only segments without LGE. ECV was considered elevated if >30%, the upper 95% bounds of a reference group without known cardiac disease (n=28). Patients were divided into 4 groups by presence of elevated ECV and of any LGE. Subsequent HF hospitalization and any death were ascertained. Their relationship with ECV was examined separately and as a composite with Cox proportional hazard models.Results:Of 1604 serial patients with T1 maps, 1255 were eligible after exclusions and followed over a median 26.3 (interquartile range, 15.9–37.5) months. Patients with elevated ECV had increased risk for death (hazard ratio [HR] 2.45 [95% CI, 1.76–3.41]), HF hospitalization (HR, 2.45 [95% CI, 1.77–3.40]), and a combined end point of both outcomes (HR, 2.46 [95% CI, 1.94–3.14]). After adjustments for covariates including LGE, the relationship persisted for death (HR, 1.82 [95% CI, 1.28–2.59]), hospitalization (HR, 1.60 [95% CI, 1.12–2.27]), and combined end points (HR, 1.73 [95% CI, 1.34–2.24]).Conclusions:ECV measures of diffuse myocardial fibrosis were associated with HF outcomes, despite exclusion of replacement fibrosis segments from their derivation and even among patients without any scar. ECV may have a synergistic role with LGE in HF risk assessment.

  • Echocardiographic Assessment of Cardiac Function in Pediatric Survivors of Anthracycline-Treated Childhood Cancer
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-12-12
    Martijn G. Slieker; Cheryl Fackoury; Cameron Slorach; Wei Hui; Mark K. Friedberg; Chun-Po Steve Fan; Cedric Manlhiot; Rejane Dillenburg; Paul Kantor; Seema Mital; Peter Liu; Paul C. Nathan; Luc Mertens

    Background:Anthracycline-induced cardiotoxicity is a major cause of morbidity and mortality in childhood cancer survivors (CCSs). Echocardiographic myocardial strain imaging is recommended in adult patients with cancer, but its role in pediatric CCSs has not been well established. Aims of this study were to determine the prevalence of abnormalities in left ventricular strain in pediatric CCSs, to compare strain with other echocardiographic measurements and blood biomarkers, and to explore risk factors for reduced strain.Methods:CCSs ≥3 years from their last anthracycline treatment were enrolled in this multicenter study and underwent a standardized functional echocardiogram and biomarker collection. Regression analysis was used to identify factors associated with longitudinal strain (LS).Results:Five hundred forty-six pediatric CCSs were compared with 134 healthy controls. Abnormal left ventricular ejection fraction (<50%) and mean LS (Z score, <−2) was found in 0.8% and 7.7% of the CCSs, respectively. LS was significantly lower in CCSs than in controls, but the absolute difference was small (0.7%). Lower LS in CCSs was associated with older current age and higher body surface area. Sex, cumulative anthracycline dose, radiotherapy, and biomarkers were not independently associated with LS. Circumferential strain, diastolic parameters, and biomarkers were not significantly different in pediatric CCSs.Conclusions:Global systolic function and LS are only mildly reduced in pediatric CCSs, and most LS values are within normal range. This makes single LS measurements of limited added value in identifying CCSs at risk for cardiac dysfunction. The utility of strain imaging in the long-term follow-up of CCS remains to be demonstrated.

  • Myocardial Storage, Inflammation, and Cardiac Phenotype in Fabry Disease After One Year of Enzyme Replacement Therapy
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-12-12
    Sabrina Nordin; Rebecca Kozor; Ravi Vijapurapu; João B. Augusto; Kristopher D. Knott; Gabriella Captur; Thomas A. Treibel; Uma Ramaswami; Michel Tchan; Tarekegn Geberhiwot; Richard P. Steeds; Derralynn A. Hughes; James C. Moon

    Background:Cardiac response to enzyme replacement therapy (ERT) in Fabry disease is typically assessed by measuring left ventricular mass index using echocardiography or cardiovascular magnetic resonance, but neither quantifies myocardial biology. Low native T1 in Fabry disease represents sphingolipid accumulation; late gadolinium enhancement with high T2 and troponin elevation reflects inflammation. We evaluated the effect of ERT on myocardial storage, inflammation, and hypertrophy.Methods:Twenty patients starting ERT (60% left ventricular hypertrophy–positive) were compared with 18 patients with early disease and 18 with advanced disease over 1 year at 3 centers. Cardiovascular magnetic resonance (left ventricular mass index, T1, T2, global longitudinal strain, and late gadolinium enhancement) and biomarkers (high-sensitive troponin-T and NT-proBNP [N-terminal Pro-B-type natriuretic peptide]) at baseline (pre-ERT) and 12 months were performed. Early disease controls were stable, treatment-naïve patients (mainly left ventricular hypertrophy–negative); advanced disease controls were stable, established ERT patients (mainly left ventricular hypertrophy–positive).Results:Over 1 year, early disease controls increased maximum wall thickness and left ventricular mass index (9.8±2.7 versus 10.2±2.6 mm; P=0.010; 65±15 versus 67±16 g/m2; P=0.005) and native T1 fell (981±58 versus 959±61 ms; P=0.002). Advanced disease controls increased T2 in the late gadolinium enhancement area (57±6 versus 60±7 ms; P=0.023) with worsening global longitudinal strain (−13.2±3.4 versus −12.1±4.8; P=0.039). Newly treated patients had a small reduction in maximum wall thickness (14.8±5.9 versus 14.4±5.7 mm; P=0.028), stable left ventricular mass index (93±42 versus 92±40 g/m2; P=0.186) and a reduction in T1 lowering (917±49 versus 931±54 ms; P=0.017).Conclusions:Fabry myocardial phenotype development is different at different disease stages. After 1 year of ERT initiation, left ventricular hypertrophy–positive patients have a detectable, small reduction in left ventricular mass and storage.

  • Hemodynamics and Subclinical Leaflet Thrombosis in Low-Risk Patients Undergoing Transcatheter Aortic Valve Replacement
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-12-12
    Jaffar M. Khan; Toby Rogers; Ron Waksman; Rebecca Torguson; Gaby Weissman; Diego Medvedofsky; Paige E. Craig; Cheng Zhang; Paul Gordon; Afshin Ehsan; Sean R. Wilson; John Goncalves; Robert Levitt; Chiwon Hahn; Puja Parikh; Thomas Bilfinger; David Butzel; Scott Buchanan; Nicholas Hanna; Robert Garrett; Christian Shults; Hector M. Garcia-Garcia; Paul Kolm; Lowell F. Satler; Maurice Buchbinder; Itsik Ben-Dor; Federico M. Asch

    Background:This analysis evaluated echocardiographic predictors of hypoattenuated leaflet thickening (HALT) in low-risk patients undergoing transcatheter aortic valve replacement and assessed 1-year clinical and hemodynamic consequences. HALT by computed tomography may be associated with early valve degeneration and increased neurological events.Methods:Echocardiograms were performed at baseline, discharge, 30 days, and 1 year post-procedure. Four-dimensional contrast-enhanced computed tomography assessed HALT at 30 days. Independent core laboratories analyzed images. Doppler hemodynamic parameters were tested in a univariable regression model to identify HALT predictors. One-year clinical and hemodynamic outcomes were compared between HALT (+) and (−) patients.Results:Analysis included 170 patients with Sapien 3 valves and diagnostic 30-day computed tomographies, of whom 27 (16%) had HALT. Baseline characteristics were similar between groups. After transcatheter aortic valve replacement, aortic flow was nonsignificantly reduced in patients who developed HALT. Regression analysis did not show significant association between baseline or discharge valve hemodynamics and development of HALT at 30 days. Patients with HALT had smaller aortic valve areas (1.4±0.4 versus 1.7±0.5 cm2; P=0.018) and Doppler velocity index (0.4±0.1 versus 0.5±0.1; P=0.003) than those without HALT at 30 days but not at 1 year. There was no difference in aortic mean gradient at 30 days. There was no difference between the groups in New York Heart Association class, 6-minute walk distance, and mortality at 1 year.Conclusions:There were no early hemodynamic predictors of HALT. At 30 days, patients with HALT had worse valve hemodynamics than those without HALT, but hemodynamic and clinical outcomes at 1 year were similar.Clinical Trial Registration:URL: http://www.clinicaltrials.gov. Unique identifier: NCT02628899.

  • Impact of Aortomitral Continuity Calcification on Need for Permanent Pacemaker After Transcatheter Aortic Valve Replacement
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-12-09
    Farhan Katchi, Deep Bhatt, Steven M. Markowitz, Jackie Szymonifka, Edward P. Cheng, Robert M. Minutello, Geoffrey W. Bergman, S. Chiu Wong, Arash Salemi, Quynh A. Truong

    Background:By virtue of its proximity to structures vital to cardiac conduction, aortomitral continuity calcification (AMCC) may help identify patients at highest risk for developing atrioventricular conduction disease requiring permanent pacemaker implantation (PPMI). We aim to determine the association of AMCC and need for PPMI after transcatheter aortic valve replacement.Methods:Of 614 patients who underwent transcatheter aortic valve replacement (11.8% PPMI rate), we included 136 patients (age 85±8 years, 47% male) without a preexisting intracardiac device or prior valve surgery who underwent preprocedural computed tomography. We analyzed for the presence of AMCC, aortic valve calcification, and mitral annular calcification as well as quantified AMCC and aortic valve calcification score using the Agatston method. We further stratified AMCC score into 3 categories: 0, 1 to 300, and >300. End point was PPMI at 1 month after transcatheter aortic valve replacement.Results:There were 51 (38%) new PPMIs (median time to PPMI, 5 days). Patients who underwent PPMI had a higher prevalence of AMCC than patients without PPMI (69% versus 32%; P<0.0001), as well as higher median AMCC score (263 versus 0; P<0.0001). There was no difference in aortic valve calcification and mitral annular calcification between patients with and without PPMI (all P≥0.09). Patients with AMCC had a 4-fold increase in odds for PPMI compared with those without (adjusted odds ratio, 4.0; P=0.0026). Compared with patients with an AMCC score of 0, patients with an AMCC score >300 had greater than a 5-fold increased odds for PPMI (adjusted odds ratio, 5.7; P=0.0016).Conclusions:Presence of AMCC, particularly with AMCC score >300, is associated with the need for PPMI after transcatheter aortic valve replacement.

  • Value of Computed Tomography Radiomic Features for Differentiation of Periprosthetic Mass in Patients With Suspected Prosthetic Valve Obstruction
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-11-19
    Kyungsun Nam, Young Joo Suh, Kyunghwa Han, Sang Joon Park, Young Jin Kim, Byoung Wook Choi

    Background:We aimed to determine whether quantitative computed tomography radiomic features can aid in differentiating between the causes of prosthetic valve obstruction (PVO) in patients who had undergone prosthetic valve replacement.Methods:This retrospective study included 39 periprosthetic masses in 34 patients who underwent cardiac computed tomography scan from January 2014 to August 2017 and were clinically suspected as PVO. The cause of PVO was assessed by redo-surgery and follow-up imaging as standard reference, and classified as pannus, thrombus, or vegetation. Visual analysis was performed to assess the possible cause of PVO on axial and valve-dedicated views. Computed tomography radiomic analysis of periprosthetic masses was performed and radiomic features were extracted. The advantage of radiomic score compared with visual analysis for differentiation of pannus from other abnormalities was assessed.Results:Of 39 masses, there were 20 cases of pannus, 11 of thrombus, and 8 of vegetation on final diagnosis. The radiomic score was significantly higher in the pannus group compared with nonpannus group (mean, −0.156±0.422 versus −0.883±0.474; P<0.001). The area under the curve of radiomic score for diagnosis of pannus was 0.876 (95% CI, 0.731–0.960). Combination of radiomic score and visual analysis showed a better performance for the differentiation of pannus than visual analysis alone.Conclusions:Compared with visual analysis, computed tomography radiomic features may have added value for differentiating pannus from thrombus or vegetation in patients with suspected PVO.

  • Peri-Infarct Quantification by Cardiac Magnetic Resonance to Predict Outcomes in Ischemic Cardiomyopathy
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-11-18
    Hourmazd Haghbayan, Nick Lougheed, Djeven P. Deva, Kelvin K.W. Chan, João A.C. Lima, Andrew T. Yan

    Background:In ischemic cardiomyopathy, cardiac magnetic resonance assessment of the peri-infarct zone, a potential substrate for arrhythmogenesis, may serve as a novel prognosticator and guide the optimal use of implantable cardioverter-defibrillators. We undertook a systematic review and meta-analysis assessing the prognostic value of the peri-infarct zone on late gadolinium enhancement cardiac magnetic resonance in ischemic cardiomyopathy.Methods:We searched MEDLINE (Medical Literature Analysis and Retrieval System Online), EMBASE (Medical Literature Analysis and Retrieval System Online), and CENTRAL (Medical Literature Analysis and Retrieval System Online) from inception to January 2019 for prognostic studies relating peri-infarct size with clinical outcomes in ischemic cardiomyopathy. Two authors independently performed study selection and data extraction. Pooled effect estimates were calculated with random effects models, risk of bias and strength of evidence were assessed by the Quality in Prognostic Studies tool and Grading of Recommendations Assessment, Development, and Education, respectively.Results:Twenty studies were eligible, representing 14 cohort studies (n=1518) with mean follow-up of 3.6 years and 6 cross-sectional studies (n=189). The extent of the peri-infarct zone was significantly predictive of all-cause mortality (3 studies; n=539; hazard ratio, 1.34/10 g [95% CI, 1.13–1.59]; I2=0%; high-quality evidence), appropriate implantable cardioverter-defibrillator therapy (5 studies; n=361; hazard ratio, 1.31/10 g [95% CI, 1.17–1.47]; I2=0%; high-quality evidence), and inducibility of ventricular tachycardia on electrophysiological study (5 studies; n=167; OR, 2.63/g [95% CI, 1.39–4.96]; I2=14%; low-quality evidence). After adjusting for age and left ventricular ejection fraction, the peri-infarct zone, as a percentage of total infarct size, remained an independent predictor of all-cause mortality (2 studies; n=445; hazard ratio, 1.29/10% [95% CI, 1.15–1.44]; I2=0%; high-quality evidence).Conclusions:There is limited but consistent evidence that quantification of the peri-infarct zone predicts long-term mortality and appropriate implantable cardioverter-defibrillator therapy in ischemic cardiomyopathy. Future studies should confirm whether late gadolinium enhancement-cardiac magnetic resonance assessment may improve implantable cardioverter-defibrillator treatment decisions.Clinical Trial Registration:URL: https://www.crd.york.ac.uk/prospero/. Unique identifier: CRD42017077337.

  • Multimodality Imaging Assessment of Fabry Disease
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-11-13
    Albree Tower-Rader, Wael A. Jaber

    Fabry disease is a lysosomal storage disease with a variety of cardiac manifestations. Although not specific for a diagnosis of Fabry disease, certain cardiac imaging findings may be highly suggestive of the diagnosis of Fabry disease in previously undiagnosed patients or cardiac involvement for patients with a known diagnosis of Fabry disease. In this review, we explore the current applications of multimodality cardiac imaging in the diagnosis and monitoring of patients with Fabry disease. Additionally, data regarding tissue characterization by cardiac magnetic resonance imaging and novel nuclear imaging techniques and their role in evaluating phenotype development is discussed.

  • Postprandial Vascular Dysfunction Is Associated With Raised Blood Pressure and Adverse Left Ventricular Remodeling in Adolescent Adiposity
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-11-11
    Jakob A. Hauser, Vivek Muthurangu, Naveed Sattar, Andrew M. Taylor, Alexander Jones

    Background:Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular disease, including heart failure. Although linked to obesity and hypertension, its pathogenesis is multifactorial. Blunted postprandial sympathetic regulation of gut blood flow has been observed in overweight animals and suggested as a promotor of hypertension and LVH. We hypothesized that blunted postprandial superior mesenteric blood flow responses would be more common in overweight humans and associated with increased blood pressure and LVH.Methods:Left ventricular dimensions and hemodynamic responses to a standardized high-calorie liquid meal were measured in healthy adolescents (n=82; 39 overweight/obese) by magnetic resonance imaging. Covariates such as body mass index, blood pressure, Tanner score, and an index of insulin resistance were included in multiple regression models to examine the independent associations of mesenteric flow response with blood pressure status and LVH.Results:Food ingestion increased cardiac output (Δmean, 0.45 [SD, 0.62] L·min−1; P=3.8×10−8) and superior mesenteric artery flow (Δmean, 0.76 [SD, 0.35] L·min−1; P=4.2×10−31). A blunted mesenteric flow response was associated with increased left ventricular mass (B=−12.7 g·m−2.7 per L·min−1·m−0.92; P=6×10−5) and concentric LVH (log likelihood, −9.9; P=0.001), independently of known determinants of LVH, including body mass index. It was also associated with elevated systolic blood pressure (B=−18.0 mm Hg per L·min−1·m−0.92; P=0.001), but this link did not explain the association with left ventricular mass.Conclusions:Postprandial mesenteric vascular dysfunction is associated with LVH and hypertension, independently of common risk factors for those conditions. These findings highlight a new, independent marker of cardiovascular risk in the young.

  • Long-Term Embolic Outcomes After Detection of Left Ventricular Thrombus by Late Gadolinium Enhancement Cardiovascular Magnetic Resonance Imaging
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-11-11
    Pratik S. Velangi, Christopher Choo, Ko-Hsuan A. Chen, Felipe Kazmirczak, Prabhjot S. Nijjar, Afshin Farzaneh-Far, Osama Okasha, Mehmet Akçakaya, Jonathan W. Weinsaft, Chetan Shenoy

    Background:Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging is more sensitive than echocardiography for the detection of intracardiac thrombus because of its unique ability to identify thrombus based on tissue characteristics related to avascularity. The long-term prognostic significance of left ventricular (LV) thrombus detected by LGE CMR is unknown.Methods:We performed a matched cohort study of consecutive adult patients with LV thrombus detected by LGE CMR who were matched on the date of CMR, age, and LV ejection fraction to up to 3 patients without LV thrombus. We investigated the long-term incidence of a composite of embolic events: stroke, transient ischemic attack, or extracranial systemic arterial embolism. We also compared outcomes among patients with LV thrombus detected by LGE CMR stratified by whether the LV thrombus was also detected by echocardiography or not.Results:Of 157 LV thrombus patients, 155 were matched to 400 non-LV thrombus patients. During a median follow-up of 3.3 years, the cumulative incidence of embolism was significantly higher in LV thrombus patients compared with the matched non-LV thrombus patients (P<0.001), with annualized rates of 3.7% and 0.8% for LV thrombus and matched non-LV thrombus patients, respectively. LV thrombus was the only independent predictor of the composite embolic end point (hazard ratio, 3.99 [95% CI, 1.54–10.35]; P=0.004). The cumulative incidence of embolism was not different in patients with LV thrombus that was also detected by echocardiography versus patients with LV thrombus not detected by echocardiography (P=0.25).Conclusions:Despite contemporary antithrombotic treatment, LV thrombus detected by LGE CMR is associated with a 4-fold higher long-term incidence of embolism compared with matched non-LV thrombus patients. LV thrombus detected by LGE CMR but not by echocardiography is associated with a similar risk of embolism as that detected by both LGE CMR and echocardiography.

  • Application of Hybrid Matrix Metalloproteinase-Targeted and Dynamic 201Tl Single-Photon Emission Computed Tomography/Computed Tomography Imaging for Evaluation of Early Post-Myocardial Infarction Remodeling
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-11-11
    Stephanie L. Thorn, Shayne C. Barlow, Attila Feher, Mitchel R. Stacy, Heather Doviak, Julia Jacobs, Kia Zellars, Jennifer M. Renaud, Ran Klein, Robert A. deKemp, Aarif Y. Khakoo, TaeWeon Lee, Francis G. Spinale, Albert J. Sinusas

    Background:The induction of matrix metalloproteinases (MMPs) and reduction in tissue inhibitors of MMPs (TIMPs) plays a role in ischemia/reperfusion (I/R) injury post-myocardial infarction (MI) and subsequent left ventricular remodeling. We developed a hybrid dual isotope single-photon emission computed tomography/computed tomography approach for noninvasive evaluation of regional myocardial MMP activation with 99mTc-RP805 and dynamic 201Tl for determination of myocardial blood flow, to quantify the effects of intracoronary delivery of recombinant TIMP-3 (rTIMP-3) on I/R injury.Methods:Studies were performed in control pigs (n=5) and pigs following 90-minute balloon occlusion–induced ischemia/reperfusion (I/R) of left anterior descending artery (n=9). Before reperfusion, pigs with I/R were randomly assigned to intracoronary infusion of rTIMP-3 (1.0 mg/kg; n=5) or saline (n=4). Three days post-I/R, dual isotope imaging was performed with 99mTc-RP805 and 201Tl along with contrast cineCT to assess left ventricular function.Results:The ischemic to nonischemic ratio of 99mTc-RP805 was significantly increased following I/R in saline group (4.03±1.40), and this ratio was significantly reduced with rTIMP-3 treatment (2.22±0.57; P=0.03). This reduction in MMP activity in the MI-rTIMP-3 treatment group was associated with an improvement in relative MI region myocardial blood flow compared with the MI-saline group and improved myocardial strain in the MI region.Conclusions:We have established a novel hybrid single-photon emission computed tomography/computed tomography imaging approach for the quantitative assessment of regional MMP activation, myocardial blood flow, and cardiac function post-I/R that can be used to evaluate therapeutic interventions such as intracoronary delivery of rTIMP-3 for reduction of I/R injury in the early phases of post-MI remodeling.

  • Prognostic Implications of Global Longitudinal Strain by Feature-Tracking Cardiac Magnetic Resonance in ST-Elevation Myocardial Infarction
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-11-04
    Martin Reindl, Christina Tiller, Magdalena Holzknecht, Ivan Lechner, Alexander Beck, David Plappert, Michelle Gorzala, Mathias Pamminger, Agnes Mayr, Gert Klug, Axel Bauer, Bernhard Metzler, Sebastian J. Reinstadler

    Background:The high accuracy of feature-tracking cardiac magnetic resonance (CMR) imaging qualifies this novel modality as potential gold standard for myocardial strain analyses in ST-elevation myocardial infarction patients; however, the incremental prognostic validity of feature-tracking-CMR over left ventricular ejection fraction (LVEF) and myocardial damage remains unclear. This study therefore aimed to determine the value of myocardial strain measured by feature-tracking-CMR for the prediction of clinical outcome following ST-elevation myocardial infarction.Methods:This prospective observational study enrolled 451 revascularized ST-elevation myocardial infarction patients. Comprehensive CMR investigations were performed 3 (interquartile range, 2–4) days after infarction to determine LVEF, global longitudinal strain (GLS), global radial strain, and global circumferential strain as well as myocardial damage. Primary end point was a composite of death, re-infarction, and congestive heart failure (major adverse cardiac events [MACE]).Results:During a follow-up of 24 (interquartile range, 11–48) months, 46 patients (10%) experienced a MACE event. All 3 strain indices were impaired in patients with MACE (all P<0.001). However, GLS emerged as the strongest MACE prognosticator among strain parameters (area under the curve, 0.73 [95% CI, 0.69–0.77]) and was significantly better (P=0.005) than LVEF (area under the curve, 0.64 [95% CI, 0.59–0.68]). The association between GLS and MACE remained significant (P<0.001) after adjustment for global radial strain, global circumferential strain, and LVEF as well as for infarct size and microvascular obstruction. The addition of GLS to a risk model comprising LVEF, infarct size, and microvascular obstruction led to a net reclassification improvement (0.35 [95% CI, 0.14–0.55]; P<0.001).Conclusions:GLS by feature-tracking-CMR strongly and independently predicted the occurrence of medium-term MACE in contemporary revascularized ST-elevation myocardial infarction patients. Importantly, the prognostic value of GLS was superior and incremental to LVEF and CMR markers of infarct severity.

  • Myocardial Fibrosis and Prognosis in Heart Transplant Recipients
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-10-15
    Andrew Hughes, Osama Okasha, Afshin Farzaneh-Far, Felipe Kazmirczak, Prabhjot S. Nijjar, Pratik Velangi, Mehmet Akçakaya, Cindy M. Martin, Chetan Shenoy

    Background:Myocardial fibrosis is a well-described histopathologic feature in heart transplant recipients. Whether myocardial fibrosis in heart transplant recipients is independently associated with clinical outcomes is unclear. We sought to determine whether myocardial fibrosis on late gadolinium enhancement cardiovascular magnetic resonance imaging in heart transplant recipients was independently associated with all-cause death or major adverse cardiac outcomes in the long-term.Methods:Using a cohort of consecutive heart transplant recipients that had cardiovascular magnetic resonance imaging, we determined the prevalence and the patterns of myocardial fibrosis and analyzed associations between myocardial fibrosis and a composite end point of all-cause death or major adverse cardiac events: retransplantation, nonfatal myocardial infarction, coronary revascularization, and heart failure hospitalization.Results:One hundred and fifty-two heart transplant recipients (age, 54±15 years; 29% women; 5.0±5.4 years after heart transplantation) were included. Myocardial fibrosis was present in 18% (37% infarct pattern, 41% noninfarct pattern, and 22% both). Its prevalence was positively associated with cardiac allograft vasculopathy grade. With a median follow-up of 2.6 years, myocardial fibrosis was independently associated with all-cause death or major adverse cardiac events (hazard ratio, 2.88; 95% CI, 1.59–5.23; P<0.001) after adjustment for cardiac allograft vasculopathy, history of rejection, time since transplantation, left ventricular ejection fraction, and indexed right ventricular end-diastolic volume. Every 1% increase in myocardial fibrosis was independently associated with a 6% higher hazard for all-cause death or major adverse cardiac events (hazard ratio, 1.06; 95% CI, 1.03–1.09; P<0.001). The addition of myocardial fibrosis variables to models with cardiac allograft vasculopathy, history of rejection, time since transplantation, left ventricular ejection fraction, and indexed right ventricular end-diastolic volume resulted in significant improvements in model fit, suggesting incremental prognostic value.Conclusions:In heart transplant recipients, myocardial fibrosis is seen on late gadolinium enhancement cardiovascular magnetic resonance imaging in 18%. Both the presence and the extent of myocardial fibrosis are independently associated with the long-term risk of all-cause death or major adverse cardiac events.

  • Performance of Traditional Pretest Probability Estimates in Stable Patients Undergoing Myocardial Perfusion Imaging
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-10-14
    Omar Batal, Saurabh Malhotra, Matthew Harinstein, Jeremy Markowitz, Gavin Hickey, Sunil Agarwal, Pamela Douglas, Prem Soman

    Background:The yield of myocardial perfusion imaging is low in contemporary patients with suspected coronary artery disease (CAD) selected based on American College of Cardiology Foundation/American Heart Association pretest probability estimate. We compared traditional pretest estimates of CAD probability with the prevalence of abnormal myocardial perfusion single-photon emission computed tomography (MPS).Methods:This was a cohort study from a single academic center. Consecutive stable patients without known CAD referred for stress MPS for suspected CAD between 2004 and 2011 were identified (n=15 777). Angina typicality was determined using standard criteria. Abnormal MPS perfusion was defined as a summed stress score ≥4, ischemia as summed stress score ≥4 and summed difference score ≥2, and extensive ischemia as summed difference score ≥8 using a standard, 17-segment model of the left ventricle. The pretest probability of CAD was determined using the American College of Cardiology Foundation/American Heart Association criteria.Results:Overall, 14% (n=2177) of patients had abnormal MPS of whom 11% (n=1698) had ischemia and 4% (n=684) extensive ischemia. In patients with chest pain who underwent treadmill MPS (n=4764), only 27% reported angina on the treadmill. Typical angina was associated with the highest prevalence for positive MPS (33% in men and 14% in women), ischemia (30% in men and 12% in women), and extensive ischemia (22% in men and 4% in women) when compared with other symptom categories. Prevalence of MPS abnormality was substantially lower than expected based on pretest probability estimates across most sex and age groups. In multivariable analysis, the pretest probability estimate was not an independent predictor of abnormal MPS.Conclusions:Traditional estimates of pretest probability of CAD are not predictive of MPS perfusion abnormality and overestimate its prevalence in stable patients.

  • Prognostic Value of Low Flow in Patients With High Transvalvular Gradient Severe Aortic Stenosis and Preserved Left Ventricular Ejection Fraction
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-10-10
    Sylvestre Maréchaux, Dan Rusinaru, Alexandre Altes, Agnès Pasquet, Jean Louis Vanoverschelde, Christophe Tribouilloy

    Background:Grading of severe (aortic valve area ≤1 cm2) aortic stenosis with preserved left ventricular ejection fraction is based on a classification depending on flow (normal flow versus low flow) and pressure gradient (low gradient versus high gradient). The aim of the present study was to compare the outcome of patients with normal flow high gradient and low flow high gradient severe aortic stenosis (SAS) with no or minimal symptoms.Methods:This multicenter study enrolled 983 consecutive patients (mean age 75±11 years, 459 women) with asymptomatic or minimally symptomatic HG (mean pressure gradient ≥40 mm Hg) SAS with preserved left ventricular ejection fraction. Low flow was defined by Doppler echocardiography as a stroke volume index <30 mL/m2 (n=131) or a stroke volume <55 mL (n=136). The end point was all-cause mortality.Results:During a median follow-up period of 48 (45–52) months, 225 patients (23%) died. The 60–month mortality was higher in low flow high gradient SAS compared with normal flow high gradient SAS (36±5% versus 22±2% and 38±5% versus 21±2% for stroke volume index and stroke volume, respectively, both P<0.0001). After adjustment for outcome predictors including aortic valve replacement as time-dependent covariate, low flow high gradient SAS displayed considerable mortality risk during follow up compared with normal flow high gradient SAS (adjusted HR 2.17 [1.51–3.13]; P<0.0001 for stroke volume index <30 mL/m2 and adjusted HR 1.86 [1.29–2.68]; P=0.001, for stroke volume <55 mL). The prognostic impact of low flow was consistent in subgroups of patients.Conclusions:Asymptomatic or minimally symptomatic patients with low flow high gradient SAS and preserved left ventricular ejection fraction have a considerable increased risk of mortality during follow-up. These patients should be promptly considered for aortic valve replacement.

  • Patient-Specific Computer Simulation of Transcatheter Aortic Valve Replacement in Bicuspid Aortic Valve Morphology
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-10-09
    Cameron Dowling, Alessandra M. Bavo, Nahid El Faquir, Peter Mortier, Peter de Jaegere, Ole De Backer, Lars Sondergaard, Philipp Ruile, Darren Mylotte, Hannah McConkey, Ronak Rajani, Jean-Claude Laborde, Stephen J. Brecker

    Background:A patient-specific computer simulation of transcatheter aortic valve replacement (TAVR) in tricuspid aortic valve has been developed, which can predict paravalvular regurgitation and conduction disturbance. We wished to validate a patient-specific computer simulation of TAVR in bicuspid aortic valve and to determine whether patient-specific transcatheter heart valve (THV) sizing and positioning might improve clinical outcomes.Methods:A retrospective study was performed on TAVR in bicuspid aortic valve patients that had both pre- and postprocedural computed tomography imaging. Preprocedural computed tomography imaging was used to create finite element models of the aortic root. Finite element analysis and computational fluid dynamics was performed. The simulation output was compared with postprocedural computed tomography imaging, cineangiography, echocardiography, and electrocardiograms. For each patient, multiple simulations were performed, to identify an optimal THV size and position for the patient’s specific anatomic characteristics.Results:A total of 37 patients were included in the study. The simulations accurately predicted the THV frame deformation (minimum-diameter intraclass correlation coefficient, 0.84; maximum-diameter intraclass correlation coefficient, 0.88; perimeter intraclass correlation coefficient, 0.91; area intraclass correlation coefficient, 0.91), more than mild paravalvular regurgitation (area under the receiver operating characteristic curve, 0.86) and major conduction abnormalities (new left bundle branch block or high-degree atrioventricular block; area under the receiver operating characteristic curve, 0.88). When compared with the implanted THV size and implant depth, optimal patient-specific THV sizing and positioning reduced simulation-predicted paravalvular regurgitation and markers of conduction disturbance.Conclusions:Patient-specific computer simulation of TAVR in bicuspid aortic valve may predict the development of important clinical outcomes, such as paravalvular regurgitation and conduction abnormalities. Patient-specific THV sizing and positioning may improve clinical outcomes of TAVR in bicuspid aortic valve.

  • Reverse Remodeling of the Mitral Valve Complex After Radiofrequency Catheter Ablation for Atrial Fibrillation
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-10-09
    Shun Nishino, Nozomi Watanabe, Keiichi Ashikaga, Kenji Morihisa, Nehiro Kuriyama, Yujiro Asada, Yoshisato Shibata

    Background:Mitral regurgitation is frequently complicated with atrial fibrillation without apparent organic changes in the leaflet, which occasionally improves after successful radiofrequency catheter ablation. We aimed to evaluate a possible geometric effect of radiofrequency catheter ablation on the mitral valve apparatus.Methods:Forty-three consecutive patients who underwent successful catheter ablation for persistent atrial fibrillation (maintaining sinus rhythm for 6 months after their procedure) were examined by serial real-time 3-dimensional transesophageal echocardiography before and 6 months after catheter ablation. Mitral valve complex geometry was measured using dedicated software for 3-dimensional transesophageal echocardiography.Results:Mitral valve apparatus showed significant reverse remodeling along with left atrial reverse remodeling 6 months after successful catheter ablation (50.5 [39.2–61.0] versus 36.4 [28.9–43.1] mL/m2; P<0.001). The degree of mitral regurgitation decreased in a majority of patients (mitral regurgitation jet area; 1.83 [0.78–3.09] versus 0.77 [0.36–1.47] cm2; P<0.001). Annular area significantly decreased (5.32±0.91 versus 4.73±0.76 cm2/m2; P<0.001) in both anterior-posterior and medial-lateral directions. Mitral annular contraction significantly recovered after maintaining sinus rhythm for 6 months (7.51 [4.82–9.62]% versus 9.71 [6.27–13.85]%; P=0.008). There were no significant changes in tenting volume or tenting height (0.46 [0.27–0.89] versus 0.51 [0.32–0.72] mL/m2, P=0.744; 2.34 [1.75–3.48] versus 2.76 [1.99–3.08] mm/m2, P=0.717). The leaflet surface area also significantly decreased after catheter ablation (5.74 [5.01–6.33] versus 5.19 [4.63–5.64] cm2/m2; P<0.001).Conclusions:Maintaining sinus rhythm after successful catheter ablation promotes reverse remodeling in the mitral valve apparatus and improves so-called atrial functional mitral regurgitation. The positive geometric effect of catheter ablation would be expected to be a possible contributor to better outcomes in patients with atrial fibrillation, in addition to the postprocedural freedom from rhythm disturbance.

  • Three-Dimensional Printing Applications in Percutaneous Structural Heart Interventions
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-10-09
    Serge C. Harb, Leonardo L. Rodriguez, Marija Vukicevic, Samir R. Kapadia, Stephen H. Little

    Cardiovascular 3-dimensional printing refers to the fabrication of patients’ specific cardiac anatomic replicas based on volumetric imaging data sets obtained by echocardiography, computed tomography, or magnetic resonance imaging. It enables advanced visualization and enhanced anatomic and sometimes hemodynamic understanding and also improves procedural planning and allows interventional simulation. Also, it is helpful in communication with patients and trainees. These key advantages have led to its broad use in the field of cardiology ranging from congenital to vascular and valvular disease, particularly in structural heart interventions, where many emerging technologies are being developed and tested. This review summarizes the process of 3-dimensional printing and the workflow from imaging acquisition to model generation and discusses the cardiac applications of 3-dimensional printing focusing on its use in percutaneous structural interventions, where procedural planning now commonly relies on 3-dimensional printed models.

  • A Multicenter, Scan-Rescan, Human and Machine Learning CMR Study to Test Generalizability and Precision in Imaging Biomarker Analysis
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-09-24

    Background:Automated analysis of cardiac structure and function using machine learning (ML) has great potential, but is currently hindered by poor generalizability. Comparison is traditionally against clinicians as a reference, ignoring inherent human inter- and intraobserver error, and ensuring that ML cannot demonstrate superiority. Measuring precision (scan:rescan reproducibility) addresses this. We compared precision of ML and humans using a multicenter, multi-disease, scan:rescan cardiovascular magnetic resonance data set.Methods:One hundred ten patients (5 disease categories, 5 institutions, 2 scanner manufacturers, and 2 field strengths) underwent scan:rescan cardiovascular magnetic resonance (96% within one week). After identification of the most precise human technique, left ventricular chamber volumes, mass, and ejection fraction were measured by an expert, a trained junior clinician, and a fully automated convolutional neural network trained on 599 independent multicenter disease cases. Scan:rescan coefficient of variation and 1000 bootstrapped 95% CIs were calculated and compared using mixed linear effects models.Results:Clinicians can be confident in detecting a 9% change in left ventricular ejection fraction, with greater than half of coefficient of variation attributable to intraobserver variation. Expert, trained junior, and automated scan:rescan precision were similar (for left ventricular ejection fraction, coefficient of variation 6.1 [5.2%–7.1%], P=0.2581; 8.3 [5.6%–10.3%], P=0.3653; 8.8 [6.1%–11.1%], P=0.8620). Automated analysis was 186× faster than humans (0.07 versus 13 minutes).Conclusions:Automated ML analysis is faster with similar precision to the most precise human techniques, even when challenged with real-world scan:rescan data. Assessment of multicenter, multi-vendor, multi-field strength scan:rescan data (available at www.thevolumesresource.com) permits a generalizable assessment of ML precision and may facilitate direct translation of ML to clinical practice.

  • Point of Care Clinical Risk Score to Improve the Negative Diagnostic Utility of an Agatston Score of Zero
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-09-17
    Ali M. Alshahrani, Hamza Mahmood, George A. Wells, Alomgir Hossain, Frank J. Rybicki, Stephan Achenbach, Mouaz H. Al-Mallah, Daniele Andreini, Jeroen J. Bax, Daniel S. Berman, Matthew J. Budoff, Filippo Cademartiri, Tracy Q. Callister, Hyuk-Jae Chang, Kavitha Chinnaiyan, Ricardo C. Cury, Augustin DeLago, Gudrun Feuchtner, Martin Hadamitzky, Joerg Hausleiter, Philipp A. Kaufmann, Yong-Jin Kim, Jonathon A. Leipsic, Erica Maffei, Hugo Marques, Gianluca Pontone, Gilbert Raff, Ronen Rubinshtein, Leslee J. Shaw, Todd C. Villines, Fay Y. Lin, James K. Min, Benjamin J. Chow

    Background:Coronary artery calcification is a marker of underlying atherosclerotic vascular disease. The absence of coronary artery calcification is associated with a low prevalence of obstructive coronary artery disease (CAD), but it cannot be ruled out completely. We sought to develop a clinical tool that can be added to Agatston score of zero to rule out obstructive CAD with high accuracy.Methods:We developed a clinical score retrospectively from a cohort of 4903 consecutive patients with an Agatston score of zero. Patients with prior diagnosis of CAD, coronary percutaneous coronary intervention, or surgical revascularization were excluded. Obstructive CAD was defined as any epicardial vessel diameter narrowing of ≥50%. The score was validated using an external cohort of 4290 patients with an Agatston score of zero from a multinational registry.Results:The score consisted of 7 variables: age, sex, typical chest pain, dyslipidemia, hypertension, family history, and diabetes mellitus. The model was robust with an area under the curve of 0.70 (95% CI, 0.65–0.76) in the derivation cohort and 0.69 (95% CI, 0.65–0.72) in the validation cohort. Patients were divided into 3 risk groups based on the score: low (≤6), intermediate (7–13), and high (≥14). Patients who score ≤6 have a negative likelihood ratio of 0.42 for obstructive CAD, whereas those who score ≥14 have a positive likelihood ratio of >5.5 for obstructive CAD. The outcome was ruled out in >98% of patients with a score ≤6 in the validation cohort.Conclusions:We developed a score that may be used to identify the likelihood of obstructive CAD in patients with an Agatston score of zero, which may be used to direct the need for additional testing. However, the results of this retrospective analysis are hypothesis generating and before clinical implementation should be validated in a trial with a prospectively collected data.

  • Changes in Cardiac Morphology and Function in Individuals With Diabetes Mellitus
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-09-16
    Magnus T. Jensen, Kenneth Fung, Nay Aung, Mihir M. Sanghvi, Sucharitha Chadalavada, Jose M. Paiva, Mohammed Y. Khanji, Martina C. de Knegt, Elena Lukaschuk, Aaron M. Lee, Ahmet Barutcu, Edd Maclean, Valentina Carapella, Jackie Cooper, Alistair Young, Stefan K. Piechnik, Stefan Neubauer, Steffen E. Petersen

    Background:Diabetes mellitus (DM) is associated with increased risk of cardiovascular disease. Detection of early cardiac changes before manifest disease develops is important. We investigated early alterations in cardiac structure and function associated with DM using cardiovascular magnetic resonance imaging.Methods:Participants from the UK Biobank Cardiovascular Magnetic Resonance Substudy, a community cohort study, without known cardiovascular disease and left ventricular ejection fraction ≥50% were included. Multivariable linear regression models were performed. The investigators were blinded to DM status.Results:A total of 3984 individuals, 45% men, (mean [SD]) age 61.3 (7.5) years, hereof 143 individuals (3.6%) with DM. There was no difference in left ventricular (LV) ejection fraction (DM versus no DM; coefficient [95% CI]: −0.86% [−1.8 to 0.5]; P=0.065), LV mass (−0.13 g/m2 [−1.6 to 1.3], P=0.86), or right ventricular ejection fraction (−0.23% [−1.2 to 0.8], P=0.65). However, both LV and right ventricular volumes were significantly smaller in DM, (LV end-diastolic volume/m2: −3.46 mL/m2 [−5.8 to −1.2], P=0.003, right ventricular end-diastolic volume/m2: −4.2 mL/m2 [−6.8 to −1.7], P=0.001, LV stroke volume/m2: −3.0 mL/m2 [−4.5 to −1.5], P<0.001; right ventricular stroke volume/m2: −3.8 mL/m2 [−6.5 to −1.1], P=0.005), LV mass/volume: 0.026 (0.01 to 0.04) g/mL, P=0.006. Both left atrial and right atrial emptying fraction were lower in DM (right atrial emptying fraction: −6.2% [−10.2 to −2.1], P=0.003; left atrial emptying fraction:−3.5% [−6.9 to −0.1], P=0.043). LV global circumferential strain was impaired in DM (coefficient [95% CI]: 0.38% [0.01 to 0.7], P=0.045).Conclusions:In a low-risk general population without known cardiovascular disease and with preserved LV ejection fraction, DM is associated with early changes in all 4 cardiac chambers. These findings suggest that diabetic cardiomyopathy is not a regional condition of the LV but affects the heart globally.

  • Association of Long-Term Risk Factor Levels With Carotid Atherosclerosis
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-09-16
    Jarett D. Berry, Anurag Mehta, Kai Lin, Colby R. Ayers, Timothy Carroll, Ambarish Pandey, Daniel B. Garside, Martha L. Daviglus, Chun Yuan, Donald M. Lloyd-Jones

    Background:Absence of cardiovascular risk factors (RF) in young adulthood is associated with a lower risk for cardiovascular disease. However, it is unclear if low RF burden in young adulthood decreases the quantitative burden and qualitative features of atherosclerosis.Methods:Multi-contrast carotid magnetic resonance imaging was performed on 440 Chicago Healthy Aging Study participants in 2009 to 2011, whose RF (total cholesterol, blood pressure, diabetes mellitus, and smoking) were measured in 1967 to 1973. Participants were divided into 4 groups: low-risk (with total cholesterol <200 mg/dL and no treatment, blood pressure <120/80 mm Hg and no treatment, no smoking, and no diabetes mellitus), 0 high RF but some RF unfavorable (≥1 RF above low-risk threshold but below high-risk threshold), 1 high RF (total cholesterol ≥240 mg/dL or treated, blood pressure ≥140/90 or treated, diabetes mellitus, or smoking), and 2 or more high RF. Association of baseline RF status with carotid atherosclerosis (overall mean carotid wall thickness and lipid-rich necrotic core) at follow-up was assessed.Results:Among 424 participants with evaluable carotid magnetic resonance images, the mean age was 32 years at baseline and 73 years at follow-up; 67% were male, 86% white, and 36% were low-risk at baseline. Two or more high RF status was associated with higher carotid wall thickness (0.99±0.11 mm) and lipid-rich necrotic core prevalence (30%), as compared with low-risk group (0.94±0.09 mm and 17%, respectively). Each increment in baseline RF status was associated with higher carotid wall thickness (β-coefficient, 0.015; 95% CI, 0.004–0.026) and with higher lipid-rich necrotic core prevalence at older age (odds ratio, 1.26; 95% CI, 1.00–1.58) in models adjusted for baseline RF and demographics.Conclusions:RF status in young adulthood is associated with the burden and quality of carotid atherosclerosis in older age suggesting that the decades-long protective effect of low-risk status might be mediated through a lower burden of quantitative and qualitative features of atherosclerotic plaque.

  • Automated Echocardiographic Quantification of Left Ventricular Ejection Fraction Without Volume Measurements Using a Machine Learning Algorithm Mimicking a Human Expert
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-09-16
    Federico M. Asch, Nicolas Poilvert, Theodore Abraham, Madeline Jankowski, Jayne Cleve, Michael Adams, Nathanael Romano, Ha Hong, Victor Mor-Avi, Randolph P. Martin, Roberto M. Lang

    Background:Echocardiographic quantification of left ventricular (LV) ejection fraction (EF) relies on either manual or automated identification of endocardial boundaries followed by model-based calculation of end-systolic and end-diastolic LV volumes. Recent developments in artificial intelligence resulted in computer algorithms that allow near automated detection of endocardial boundaries and measurement of LV volumes and function. However, boundary identification is still prone to errors limiting accuracy in certain patients. We hypothesized that a fully automated machine learning algorithm could circumvent border detection and instead would estimate the degree of ventricular contraction, similar to a human expert trained on tens of thousands of images.Methods:Machine learning algorithm was developed and trained to automatically estimate LVEF on a database of >50 000 echocardiographic studies, including multiple apical 2- and 4-chamber views (AutoEF, BayLabs). Testing was performed on an independent group of 99 patients, whose automated EF values were compared with reference values obtained by averaging measurements by 3 experts using conventional volume-based technique. Inter-technique agreement was assessed using linear regression and Bland-Altman analysis. Consistency was assessed by mean absolute deviation among automated estimates from different combinations of apical views. Finally, sensitivity and specificity of detecting of EF ≤35% were calculated. These metrics were compared side-by-side against the same reference standard to those obtained from conventional EF measurements by clinical readers.Results:Automated estimation of LVEF was feasible in all 99 patients. AutoEF values showed high consistency (mean absolute deviation =2.9%) and excellent agreement with the reference values: r=0.95, bias=1.0%, limits of agreement =±11.8%, with sensitivity 0.90 and specificity 0.92 for detection of EF ≤35%. This was similar to clinicians’ measurements: r=0.94, bias=1.4%, limits of agreement =±13.4%, sensitivity 0.93, specificity 0.87.Conclusions:Machine learning algorithm for volume-independent LVEF estimation is highly feasible and similar in accuracy to conventional volume-based measurements, when compared with reference values provided by an expert panel.

  • Regression of Left Ventricular Mass in Athletes Undergoing Complete Detraining Is Mediated by Decrease in Intracellular but Not Extracellular Compartments
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-09-11
    Peter P. Swoboda, Pankaj Garg, Eylem Levelt, David A. Broadbent, Ashkun Zolfaghari-Nia, A. James R. Foley, Graham J. Fent, Pei G. Chew, Louise A. Brown, Christopher E. Saunderson, Erica Dall’Armellina, John P. Greenwood, Sven Plein

    Background:Athletic cardiac remodeling can occasionally be difficult to differentiate from pathological hypertrophy. Detraining is a commonly used diagnostic test to identify physiological hypertrophy, which can be diagnosed if hypertrophy regresses. We aimed to establish whether athletic cardiac remodeling assessed by cardiovascular magnetic resonance is mediated by changes in intracellular or extracellular compartments and whether this occurs by 1 or 3 months of detraining.Methods:Twenty-eight athletes about to embark on a period of forced detraining due to incidental limb bone fracture underwent clinical assessment, ECG, and contrast-enhanced cardiovascular magnetic resonance within a week of their injury and then 1 month and 3 months later.Results:After 1 month of detraining, there was reduction in left ventricular (LV) mass (130±28 to 121±25 g; P<0.0001), increase in native T1 (1225±30 to 1239±30 ms; P=0.02), and extracellular volume fraction (24.5±2.3% to 26.0±2.6%; P=0.0007) with no further changes by 3 months. The decrease in LV mass was mediated by a decrease in intracellular compartment volume (94±22 to 85±19 mL; P<0.0001) with no significant change in the extracellular compartment volume. High LV mass index, low native T1, and low extracellular volume fraction at baseline were all predictive of regression in LV mass in the first month.Conclusions:Regression of athletic LV hypertrophy can be detected after just 1 month of complete detraining and is mediated by a decrease in the intracellular myocardial compartment with no change in the extracellular compartment. Further studies are needed in athletes with overt and pathological hypertrophy to establish whether native T1 and extracellular volume fraction may complement electrocardiography, echocardiography, cardiopulmonary exercise testing, and genetic testing in predicting the outcome of detraining.

  • Validation of the Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure Ratio for the Assessment of Right Ventricular-Arterial Coupling in Severe Pulmonary Hypertension
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-09-10
    Khodr Tello, Jun Wan, Antonia Dalmer, Rebecca Vanderpool, Hossein A. Ghofrani, Robert Naeije, Fritz Roller, Emad Mohajerani, Werner Seeger, Ulrike Herberg, Natascha Sommer, Henning Gall, Manuel J. Richter

    Background:The ratios of tricuspid annular plane systolic excursion (TAPSE)/echocardiographically measured systolic pulmonary artery pressure (PASP), fractional area change/invasively measured mean pulmonary artery pressure, right ventricular (RV) area change/end-systolic area, TAPSE/pulmonary artery acceleration time, and stroke volume/end-systolic area have been proposed as surrogates of RV-arterial coupling. The relationship of these surrogates with the gold standard measure of RV-arterial coupling (invasive pressure-volume loop-derived end-systolic/arterial elastance [Ees/Ea] ratio) and RV diastolic stiffness (end-diastolic elastance) in pulmonary hypertension remains incompletely understood. We evaluated the relationship of these surrogates with invasive pressure-volume loop-derived Ees/Ea and end-diastolic elastance in pulmonary hypertension.Methods:We performed right heart echocardiography and cardiac magnetic resonance imaging 1 day before invasive measurement of pulmonary hemodynamics and single-beat RV pressure-volume loops in 52 patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. The relationships of the proposed surrogates with Ees/Ea and end-diastolic elastance were evaluated by Spearman correlation, multivariate logistic regression, and receiver operating characteristic analyses. Associations with prognosis were evaluated by Kaplan-Meier analysis.Results:TAPSE/PASP, fractional area change/mean pulmonary artery pressure, RV area change/end-systolic area, and stroke volume/end-systolic area but not TAPSE/pulmonary artery acceleration time were correlated with Ees/Ea and end-diastolic elastance. Of the surrogates, only TAPSE/PASP emerged as an independent predictor of Ees/Ea (multivariate odds ratio: 18.6; 95% CI, 0.8–96.1; P=0.08). In receiver operating characteristic analysis, a TAPSE/PASP cutoff of 0.31 mm/mm Hg (sensitivity: 87.5% and specificity: 75.9%) discriminated RV-arterial uncoupling (Ees/Ea <0.805). Patients with TAPSE/PASP <0.31 mm/mm Hg had a significantly worse prognosis than those with higher TAPSE/PASP.Conclusions:Echocardiographically determined TAPSE/PASP is a straightforward noninvasive measure of RV-arterial coupling and is affected by RV diastolic stiffness in severe pulmonary hypertension.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT03403868.

  • Regional Variability in Longitudinal Strain Across Vendors in Patients With Cardiomyopathy Due to Increased Left Ventricular Wall Thickness
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-08-15
    Brett W. Sperry, Kimi Sato, Dermot Phelan, Richard Grimm, Milind Y. Desai, Mazen Hanna, Wael A. Jaber, Zoran B Popović

    Background:Cardiomyopathies with increased left ventricular wall thickness such as cardiac amyloidosis, septal hypertrophic cardiomyopathy (HCM), and apical HCM exhibit characteristic regional longitudinal strain (LS) patterns. However, between-vendor agreement of segmental and regional LS has not been tested in these diseases. We sought to assess LS values among vendors in specific cardiomyopathies that exhibit regional strain variation: cardiac amyloidosis, septal HCM, and apical HCM.Methods:This was a prospective, cross-sectional study of 69 patients (18 amyloidosis, 30 septal HCM, 6 apical HCM, and 15 controls) who underwent clinically indicated outpatient echocardiography at the Cleveland Clinic. Peak systolic segmental, regional (basal, mid, and apical), and global LS were evaluated using GE (EchoPAC), Siemens (Velocity Vector Imaging), and Phillips (QLab) systems in the same imaging session. Between-vendor, differences were analyzed using correlation coefficients, Bland Altman plots, and a mixed model.Results:Global LS was highly correlated among the 3 software packages and most abnormal in patients with amyloidosis (P<0.001). Regional LS analysis demonstrated that QLab software tended to produce more negative LS values, driven by differences in apical strains. EchoPAC had the greatest ability to discriminate patients with amyloidosis using regional strain values (area under the curve, 0.932) as compared with Velocity Vector Imaging and QLab (P<0.001).Conclusions:Global and regional variations in LS exist between-vendors in patients with cardiomyopathies with increased left ventricular wall thickness (amyloidosis, septal HCM, and apical HCM). It is important to be aware of these differences for diagnosis, prognosis, and serial examinations in these conditions.

  • Impact of Cumulative Smoking Exposure on Subclinical Degenerative Aortic Valve Disease in Apparently Healthy Male Workers
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-08-13
    Yasuko Yamaura, Nozomi Watanabe, Maki Shimaya, Yasuhiko Tomita, Takashi Fukaya, Kiyoshi Yoshida

    Background:Little is known regarding the impact of cumulative smoking exposure and smoking cessation on subclinical degenerative aortic valve (DAV) disease.Methods:We examined associations of smoking status, cigarette-years of smoking, and years since quitting smoking with subclinical DAV disease defined by echocardiography.Results:Of 756 apparently healthy male workers, 154 had DAV including 63 with DAV with ≥2 leaflets calcification (DAV ≥2 cal). Compared with never smokers, ever smokers had higher risk of DAV and DAV ≥2 cal; odds ratios (95% CI) were 2.883 (1.800–4.618) (p<0.001) and 5.281 (2.297–12.138) (p<0.001), respectively. Both current and former smokers had dose-dependent relationships of cigarette-years on DAV and DAV ≥2 cal (P for trend, <0.001 for both DAV, in both smokers). In current smokers with >400–≤800 and with >800 cigarette-years, odds ratios (95%CIs) were 3.201 (1.690–6.063) (p<0.001) and 5.326 (2.800–10.053) (p<0.001) for DAV, 7.460 (2.828–19.680) (p<0.001) and 8.397 (3.146–22.414) (p<0.001) for DAV ≥2 cal, respectively. In former smokers with >800 cigarette-years, odds ratios (95%CI) were 3.780 (1.970–7.254) (p<0.001) for DAV, 10.035 (3.801–26.496) (p<0.001) for DAV ≥2 cal. Compared with current smokers, former smokers with quitting smoking >10 years had significantly lower risk of DAV and DAV ≥2 cal.Conclusions:In apparently healthy male workers, DAV disease was strongly associated with smoking. Cumulative smoking exposure was associated with dose-dependent relationship on subclinical DAV disease both in current smokers and former smokers.

  • Molecular Coronary Plaque Imaging Using 18F-Fluoride
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-08-06
    Alastair J. Moss, Mhairi K. Doris, Jack P.M. Andrews, Rong Bing, Marwa Daghem, Edwin J. R. van Beek, Laura Forsyth, Anoop S.V. Shah, Michelle C. Williams, Stephanie Sellers, Jonathon Leipsic, Marc R. Dweck, Richard A. Parker, David E. Newby, Philip D. Adamson

    Background:Coronary 18F-fluoride positron emission tomography identifies ruptured and high-risk atherosclerotic plaque. The optimal method to identify, to quantify, and to categorize increased coronary 18F-fluoride uptake and determine its reproducibility has yet to be established. This study aimed to optimize the identification, quantification, categorization, and scan-rescan reproducibility of increased 18F-fluoride activity in coronary atherosclerotic plaque.Methods:In a prospective observational study, patients with multi-vessel coronary artery disease underwent serial 18F-fluoride positron emission tomography. Coronary 18F-fluoride activity was visually assessed, quantified, and categorized with reference to maximal tissue to background ratios. Levels of agreement for both visual and quantitative methods were determined between scans and observers.Results:Thirty patients (90% male, 20 patients with stable coronary artery disease, and 10 with recent type 1 myocardial infarction) underwent paired serial positron emission tomography-coronary computed tomography angiography imaging within an interval of 12±5 days. A mean of 3.7±1.8 18F-fluoride positive plaques per patient was identified after recent acute coronary syndrome, compared with 2.4±2.3 positive plaques per patient in stable coronary artery disease. The bias in agreement in maximum tissue to background ratio measurements in visually positive plaques was low between observers (mean difference, −0.01; 95% limits of agreement, −0.32 to 0.30) or between scans (mean difference, 0.06; 95% limits of agreement, −0.49 to 0.61). Good agreement in the categorization of focal 18F-fluoride uptake was achieved using visual assessment alone (κ=0.66) and further improved at higher maximum tissue to background ratio values.Conclusions:Coronary 18F-fluoride activity is a precise and reproducible metric in the coronary vasculature. The analytical performance of 18F-fluoride is sufficient to assess the prognostic utility of this radiotracer as a noninvasive imaging biomarker of plaque vulnerability.Clinical Trial Registration:URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02110303 and NCT02278211.

  • Smartphone-Based Blood Pressure Measurement Using Transdermal Optical Imaging Technology
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-08-06
    Hong Luo, Deye Yang, Andrew Barszczyk, Naresh Vempala, Jing Wei, Si Jia Wu, Paul Pu Zheng, Genyue Fu, Kang Lee, Zhong-Ping Feng

    Background:Cuff-based blood pressure measurement lacks comfort and convenience. Here, we examined whether blood pressure can be determined in a contactless manner using a novel smartphone-based technology called transdermal optical imaging. This technology processes imperceptible facial blood flow changes from videos captured with a smartphone camera and uses advanced machine learning to determine blood pressure from the captured signal.Methods:We enrolled 1328 normotensive adults in our study. We used an advanced machine learning algorithm to create computational models that predict reference systolic, diastolic, and pulse pressure from facial blood flow data. We used 70% of our data set to train these models and 15% of our data set to test them. The remaining 15% of the sample was used to validate model performance.Results:We found that our models predicted blood pressure with a measurement bias±SD of 0.39±7.30 mm Hg for systolic pressure, −0.20±6.00 mm Hg for diastolic pressure, and 0.52±6.42 mm Hg for pulse pressure, respectively.Conclusions:Our results in normotensive adults fall within 5±8 mm Hg of reference measurements. Future work will determine whether these models meet the clinically accepted accuracy threshold of 5±8 mm Hg when tested on a full range of blood pressures according to international accuracy standards.

  • Optimal Cutoff Value of Fractional Flow Reserve Derived From Coronary Computed Tomography Angiography for Predicting Hemodynamically Significant Coronary Artery Disease
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-08-01
    Yukiko Matsumura-Nakano, Tetsuma Kawaji, Hiroki Shiomi, Kanae Kawai-Miyake, Masako Kataoka, Koji Koizumi, Akira Matsuda, Kazuki Kitano, Masaharu Yoshida, Hirotoshi Watanabe, Junichi Tazaki, Takao Kato, Naritatsu Saito, Satoshi Shizuta, Koh Ono, Kaori Togashi, Takeshi Morimoto, Takeshi Kimura

    Background:The optimal cutoff value of fractional flow reserve (FFR) derived from coronary computed tomography angiography (FFRCT) remains unclear.Methods:The current study population consisted of 93 patients with 139 vessels, who had suspected coronary artery disease by computed tomography angiography and underwent invasive FFR. We evaluated diagnostic performance of FFRCT according to different FFRCT cutoff values and FFRCT ranges with invasive FFR ≤0.80 as the reference standard.Results:In per-vessel analysis, median invasive FFR was 0.85 (interquartile range, 0.75–0.90), and 57 out of 139 vessels (41%) showed hemodynamically significant stenosis (≤0.80). Median FFRCT was 0.77 (interquartile range, 0.66–0.84; mean difference [invasive FFR-FFRCT], 0.06±0.11). Per-vessel accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 73%, 95%, 59%, 61%, and 94% for the cutoff value of FFRCT ≤0.80, 81%, 86%, 78%, 73%, and 89% for FFRCT ≤0.75, and 83%, 74%, 89%, 82%, and 83% for FFRCT ≤0.70, respectively. Per-vessel accuracy across the different ranges of FFRCT ≤0.60, 0.61 to 0.70, 0.71 to 0.80, 0.81 to 0.90, and >0.90 with the cutoff value of FFRCT ≤0.80 were 95%, 74%, 32%, 93%, and 100%, respectively. Setting a gray zone of FFRCT 0.71 to 0.80 provided high positive predictive value (82%; n=42/51) in the range of FFRCT ≤0.70 and high negative predictive value (94%; n=48/51) in FFRCT >0.80.Conclusions:This study suggested that referral to invasive coronary angiography should be considered individually in the range of FFRCT 0.71 to 0.80, whereas dichotomous decision could be made in FFRCT ≤0.70 and >0.80. Future prospective studies evaluating clinical outcomes are needed to establish optimal FFRCT-based diagnostic algorithm.

  • Relationship Between Pregnancy Complications and Subsequent Coronary Artery Disease Assessed by Coronary Computed Tomographic Angiography in Black Women
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-07-01
    Julian L. Wichmann, Richard A.P. Takx, Johanna H. Nunez, Rozemarijn Vliegenthart, Katharina Otani, Sheldon E. Litwin, Pamela B. Morris, Carlo N. De Cecco, Russell D. Rosenberg, Richard R. Bayer II, Stefan Baumann, Matthias Renker, Thomas J. Vogl, Nanette K. Wenger, U. Joseph Schoepf

    Background:Maternal pregnancy complications, particularly preeclampsia and gestational diabetes mellitus, are described to increase the risk for subsequent coronary artery disease (CAD). In addition, black women are at higher risk for CAD. The objective of this study was to compare the prevalence and extent of CAD as detected by coronary computed tomographic angiography (CCTA) in black women with and without a history of prior pregnancy complications.Methods:We retrospectively evaluated patient characteristics and CCTA findings in groups of black women with a prior history of preterm delivery (n=154), preeclampsia (n=137), or gestational diabetes mellitus (n=148), and a matched control group of black women who gave birth without such complications (n=445). Univariate and multivariate analyses were performed to assess risk factors of CAD.Results:All groups with prior pregnancy complications showed higher rates of any (≥20% luminal narrowing) and obstructive (≥50% luminal narrowing) CAD (preterm delivery: 29.2% and 9.1%; preeclampsia: 29.2% and 7.3%; and gestational diabetes mellitus: 47.3% and 15.5%) compared with control women (23.8% and 5.4%). After accounting for confounding factors at multivariate analysis, gestational diabetes mellitus remained a strong risk factor of any (odds ratio, 3.26; 95% CI, 2.03–5.22; P<0.001) and obstructive CAD (odds ratio, 3.00; 95% CI, 1.55–5.80; P<0.001) on CCTA.Conclusions:Black women with a history of pregnancy complications, particularly gestational diabetes mellitus, have a higher prevalence of CAD on CCTA while only a history of gestational diabetes mellitus was independently associated with any and obstructive CAD on CCTA.

  • Noninvasive In Vivo Quantification of Adeno-Associated Virus Serotype 9–Mediated Expression of the Sodium/Iodide Symporter Under Hindlimb Ischemia and Neuraminidase Desialylation in Skeletal Muscle Using Single-Photon Emission Computed Tomography/Computed Tomography
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-07-01
    Nabil E. Boutagy, Silvia Ravera, Xenophon Papademetris, John A. Onofrey, Zhen W. Zhuang, Jing Wu, Attila Feher, Mitchel R. Stacy, Brent A. French, Brian H. Annex, Nancy Carrasco, Albert J. Sinusas

    Background:We propose micro single-photon emission computed tomography/computed tomography imaging of the hNIS (human sodium/iodide symporter) to noninvasively quantify adeno-associated virus 9 (AAV9)-mediated gene expression in a murine model of peripheral artery disease.Methods:AAV9-hNIS (2×1011 viral genome particles) was injected into nonischemic or ischemic gastrocnemius muscles of C57Bl/6J mice following unilateral hindlimb ischemia ± the α-sialidase NA (neuraminidase). Control nonischemic limbs were injected with phosphate buffered saline or remained noninjected. Twelve mice underwent micro single-photon emission computed tomography/computed tomography imaging after serial injection of pertechnetate (99mTcO4−), a NIS substrate, up to 28 days after AAV9-hNIS injection. Twenty four animals were euthanized at selected times over 1 month for ex vivo validation. Forty-two animals were imaged with 99mTcO4− ± the selective NIS inhibitor perchlorate on day 10, to ascertain specificity of radiotracer uptake. Tissue was harvested for ex vivo validation. A modified version of the U-Net deep learning algorithm was used for image quantification.Results:As quantitated by standardized uptake value, there was a gradual temporal increase in 99mTcO4− uptake in muscles treated with AAV9-hNIS. Hindlimb ischemia, NA, and hindlimb ischemia plus NA increased the magnitude of 99mTcO4− uptake by 4- to 5-fold compared with nonischemic muscle treated with only AAV9-hNIS. Perchlorate treatment significantly reduced 99mTcO4− uptake in AAV9-hNIS-treated muscles, demonstrating uptake specificity. The imaging results correlated well with ex vivo well counting (r2=0.9375; P<0.0001) and immunoblot analysis of NIS protein (r2=0.65; P<0.0001).Conclusions:Micro single-photon emission computed tomography/computed tomography imaging of hNIS-mediated 99mTcO4− uptake allows for accurate in vivo quantification of AAV9-driven gene expression, which increases under ischemic conditions or neuraminidase desialylation in skeletal muscle.

  • Diagnostic Impact of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography and White Blood Cell SPECT/Computed Tomography in Patients With Suspected Cardiac Implantable Electronic Device Chronic Infection
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-07-01
    Jérémie Calais, Aziza Touati, Nathalie Grall, Cédric Laouénan, Khadija Benali, Besma Mahida, Jonathan Vigne, Fabien Hyafil, Bernard Iung, Xavier Duval, Laurent Lepage, Dominique Le Guludec, François Rouzet

    Background:Cardiac implantable electronic devices (CIEDs) chronic infection diagnosis is challenging because the clinical presentation is frequently misleading and echocardiography may be inconclusive. The aim of this study was to evaluate the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (CT) and radiolabeled white blood cells single photon emission CT/CT in a cohort of patients who underwent both scans for suspicion of CIED infection and inconclusive routine investigations.Methods:Forty-eight consecutive patients with suspicion of CIED infection who underwent both 18F-fluorodeoxyglucose positron emission tomography/CT and white blood cell single photon emission CT/CT in a time span ≤30 days were retrospectively included. The final diagnosis of CIED infection by the endocarditis expert team was based on the modified Duke-Li classification at the end of follow-up. 18F-Fluorodeoxyglucose positron emission tomography/CT and white blood cell single photon emission CT/CT scans were independently analyzed blinded to the patients’ medical record.Results:In the overall study population, the diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were respectively 80%, 91%, 80%, and 91% for 18F-fluorodeoxyglucose positron emission tomography/CT and 60%, 100%, 100%, and 85% for white blood cell single photon emission CT/CT. Addition of a positive nuclear imaging scan as a major criterion markedly improved the Duke-Li classification at admission. Semiquantitative parameters did not allow to discriminate between definite and rejected CIED infection. Prolonged antibiotic therapy before imaging tended to decrease the sensitivity for both techniques.Conclusions:Nuclear imaging can improve the diagnostic performances of the Duke-Li score at admission in a selected population of patients with suspected CIED infection, particularly when the infection was initially graded as possible. Whenever possible, imaging should be performed before or early after antibiotic initiation.

  • Detection of Inflammatory Aortopathies Using Multimodality Imaging
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-07-01
    John P. Bois, Vidhu Anand, Nandan S. Anavekar

    Diagnosis of the inflammatory aortopathies and importantly, their distinction in the later stages of disease from genetically mediated or acquired (degenerative) aortopathy remains a challenging clinical problem. Historically, the diagnosis of inflammatory aortopathy has required tissue sampling and pathological assessment. Although histological diagnosis remains an important diagnostic criterion, the ability to obtain sufficient tissue samples is problematic and requires invasive approaches that pose important risk. Continuing refinement in the capabilities of multimodality imaging, including ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography provides important insights into the broad spectrum of disease which comprise the inflammatory aortopathies. This review examines the current and emerging role of multimodality imaging in the evaluation of aortitis.

  • Quantitative Myocardial Perfusion in Fabry Disease
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-07-01
    Kristopher D. Knott, Joao B. Augusto, Sabrina Nordin, Rebecca Kozor, Claudia Camaioni, Hui Xue, Rebecca K. Hughes, Charlotte Manisty, Louise A.E. Brown, Peter Kellman, Uma Ramaswami, Derralyn Hughes, Sven Plein, James C. Moon

    Background:Fabry disease (FD) is an X-linked lysosomal storage disease resulting in tissue accumulation of sphingolipids. Key myocardial processes that lead to adverse outcomes in FD include storage, hypertrophy, inflammation, and fibrosis. These are quantifiable by multiparametric cardiovascular magnetic resonance. Recent developments in cardiovascular magnetic resonance perfusion mapping allow rapid in-line perfusion quantification permitting broader clinical application, including the assessment of microvascular dysfunction. We hypothesized that microvascular dysfunction in FD would be associated with storage, fibrosis, and edema.Methods:A prospective, observational study of 44 FD patients (49 years, 43% male, 24 [55%] with left ventricular hypertrophy [LVH]) and 27 healthy controls with multiparametric cardiovascular magnetic resonance including vasodilator stress perfusion mapping. Myocardial blood flow (MBF) was measured and its associations with other processes investigated.Results:Compared with LVH− FD, LVH+ FD had higher left ventricular ejection fraction (73% versus 68%), more late gadolinium enhancement (85% versus 15%), and a lower stress MBF (1.76 versus 2.36 mL/g per minute). The reduction in stress MBF was more pronounced in the subendocardium than subepicardium. LVH− FD had lower stress MBF than controls (2.36 versus 3.00 mL/g per minute; P=0.002). Across all FD, late gadolinium enhancement and low native T1 were independently associated with reduced stress MBF. On a per-segment basis, stress MBF was independently associated with wall thickness, T2, extracellular volume fraction, and late gadolinium enhancement.Conclusions:FD patients have reduced perfusion, particularly in the subendocardium with greater reductions with LVH, storage, edema, and scar. Perfusion is reduced even without LVH suggesting it is an early disease marker.

  • Natural History of Myocardial Injury and Chamber Remodeling in Acute Myocarditis
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-07-01
    James A. White, Reis Hansen, Ahmed Abdelhaleem, Yoko Mikami, Mingkai Peng, Sandra Rivest, Alessandro Satriano, Steven Dykstra, Jacqueline Flewitt, Bobak Heydari, Carmen P. Lydell, Matthias G. Friedrich, Andrew G. Howarth

    Background:Cardiovascular magnetic resonance (CMR) imaging is commonly used to diagnose acute myocarditis. However, the natural history of CMR-based tissue markers and their association with left ventricular recovery is poorly explored. We prospectively investigated the natural history of CMR-based myocardial injury and chamber remodeling over 12 months in patients with suspected acute myocarditis.Methods:One hundred patients with suspected acute myocarditis were enrolled. All underwent CMR evaluations at baseline and 12 months, inclusive of T2 and late gadolinium enhancement. Blinded quantitative analyses compared left ventricular chamber volumes, function, myocardial edema, and necrosis at each time point using predefined criteria. The predefined primary outcomes were improvement in left ventricular ejection fraction ≥10% and improvement in the indexed left ventricular end diastolic volume ≥10% at 12 months.Results:The mean age was 39.9±14.5 years (82 male) with baseline left ventricular ejection fraction of 57.1±11.2%. A total of 72 patients (72%) showed late gadolinium enhancement at baseline with 57 (57%) having any T2 signal elevation. Left ventricular volumes and EF improved significantly at 12 months. Global late gadolinium enhancement extent dropped from 8.5±9.2% of left ventricular mass to 3.0±5.2% (P=0.0001) with prevalence of any late gadolinium enhancement dropping to 48%. Reductions in global T2 signal ratio occurred at 12 months (1.85±0.3 to 1.56±0.2; P=0.0001) with prevalence of T2 ratio ≥2.0 dropping to 7%. Neither marker provided associations with the primary outcomes.Conclusions:In clinically suspected acute myocarditis, significant reductions in tissue injury markers occur during the first 12 months of convalescence. Neither the presence nor extent of the investigated CMR-based tissue injury markers were predictive of our pre-defined function or remodeling outcomes at 12 months in this referral population.

  • Characteristics and Outcomes in a Contemporary Group of Patients With Suspected Significant Mitral Stenosis Undergoing Treadmill Stress Echocardiography
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-06-01
    James L. Gentry III, Parth K. Parikh, Alaa Alashi, A Marc Gillinov, Gosta B. Pettersson, L Leonardo Rodriguez, Zoran B. Popovic, Kimi Sato, Richard A. Grimm, Samir R. Kapadia, E Murat Tuzcu, Lars G. Svensson,, Brian P. Griffin, Milind Y. Desai

    Background:In contemporary patients with suspected significant mitral stenosis (MS) undergoing rest and treadmill stress echocardiography, we assessed characteristics and factors associated with longer-term survival.Methods:We studied 515 consecutive patients (asymptomatic/atypical symptoms, mean left ventricular ejection fraction 58±2%; 43% male) with suspected at least moderate MS ([1] native mitral valve [MV]: resting mean MV gradient ≥5 mm Hg or area ≤1.5 cm2 and [2] prosthetic valve: resting mean MV gradient ≥5 mm Hg or effective orifice area ≤2 cm) who underwent rest and treadmill stress echocardiography between 1/2003 and 12/2013. MS was categorized as rheumatic (n=170, 33%), postsurgical (prior mitral repair/replacement, n=245, 48%), and primary nonrheumatic (n=100, 19%). Primary outcome was all-cause mortality.Results:Mean resting MV gradient and right ventricular systolic pressure were 8.5±3 and 39±13 mm Hg. Patients achieved 95±29% age-sex predicted metabolic equivalents; peak-stress MV gradient and right ventricular systolic pressure were 17±7 and 61±14 mm Hg, respectively. At 54 days (median), 224 (44%) underwent invasive mitral procedure. At 6±4 years, 76 (15%) died. On survival analysis, primary nonrheumatic MS (hazard ratio [HR], 4.92), higher Society of Thoracic Surgeons score (HR, 1.92), lower % age-sex predicted metabolic equivalents (HR, 1.22), and higher peak-stress right ventricular systolic pressure (HR, 1.35), was associated with higher mortality, while invasive mitral procedures were associated with improved survival (HR, 0.67; all P<0.01).Conclusions:In asymptomatic patients (or with atypical symptoms) with significant MS undergoing treadmill stress echocardiography, higher mortality was associated with primary nonrheumatic MS, lower % age-sex predicted metabolic equivalents, and higher peak-stress right ventricular systolic pressure, while invasive MV procedures were associated with survival.

  • Accuracy of Myocardial Blood Flow Estimation From Dynamic Contrast-Enhanced Cardiac CT Compared With PET
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-06-01
    Adam M. Alessio, Michael Bindschadler, Janet M. Busey, William P. Shuman, James H. Caldwell, Kelley R. Branch

    BackgroundThe accuracy of absolute myocardial blood flow (MBF) from dynamic contrast-enhanced cardiac computed tomography acquisitions has not been fully characterized. We evaluate computed tomography (CT) compared with rubidium-82 positron emission tomography (PET) MBF estimates in a high-risk population.MethodsIn a prospective trial, patients receiving clinically indicated rubidium-82 PET exams were recruited to receive a dynamic contrast-enhanced cardiac computed tomography exam. The CT protocol included a rest and stress dynamic portion each acquiring 12 to 18 cardiac-gated frames. The global MBF was estimated from the PET and CT exam.ResultsThirty-four patients referred for cardiac rest-stress PET were recruited. Of the 68 dynamic contrast-enhanced cardiac computed tomography scans, 5 were excluded because of injection errors or mismatched hemodynamics. The CT-derived global MBF was highly correlated with the PET MBF (r=0.92; P<0.001) with a mean difference of 0.7±26.4%. The CT MBF estimates were within 20% of PET estimates (P<0.02) with a mean of (1) MBF for resting flow of PET versus CT of 0.9±0.3 versus 1.0±0.2 mL/min per gram and (2) MBF for stress flow of 2.1±0.7 versus 2.0±0.8 mL/min per gram. Myocardial flow reserve was −14±28% underestimated with CT (PET versus CT myocardial flow reserve, 2.5±0.6 versus 2.2±0.6). The proposed rest+stress+computed tomography angiography protocol had a dose length product of 598±76 mGy×cm resulting in an approximate effective dose of 8.4±1.1 mSv.ConclusionsIn a high-risk clinical population, a clinically practical dynamic contrast-enhanced cardiac computed tomography provided unbiased MBF estimates within 20% of rubidium-82 PET. Although unbiased, the CT estimates contain substantial variance with an standard error of the estimate of 0.44 mL/min per gram. Myocardial flow reserve estimation was not as accurate as individual MBF estimates.

  • Coronary Artery Calcium From Early Adulthood to Middle Age and Left Ventricular Structure and Function
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-06-01
    Guilherme S. Yared, Henrique T. Moreira, Bharath Ambale-Venkatesh, Henrique D. Vasconcellos, Chike C. Nwabuo, Mohammad R. Ostovaneh, Jared P. Reis, Donald M. Lloyd-Jones, Pamela J. Schreiner, Cora E. Lewis, Stephen Sidney, John J. Carr, Samuel S. Gidding, João A.C. Lima

    BackgroundThe relationship of coronary artery calcium (CAC) with adverse cardiac remodeling is not well established. We aimed to study the association of CAC in middle age and change in CAC from early adulthood to middle age with left ventricular (LV) function.MethodsCAC score was measured by computed tomography at CARDIA study (Coronary Artery Risk Development in Young Adults) year-15 examination and at year-25 examination (Y25) in 3043 and 3189 participants, respectively. CAC score was assessed as a continuous variable and log-transformed to account for nonlinearity. Change in CAC from year-15 examination to Y25 was evaluated as the absolute difference of log-transformed CAC from year-15 examination to Y25. LV structure and function were evaluated by echocardiography at Y25.ResultsAt Y25, mean age was 50.1±3.6 years, 56.6% women, 52.4% black. In the multivariable analysis at Y25, higher CAC was related to higher LV mass (β=1.218; adjusted P=0.007), higher LV end-diastolic volume (β=0.811; adjusted P=0.007), higher LV end-systolic volume (β=0.350; adjusted P=0.048), higher left atrial volume (β=0.214; adjusted P=0.009), and higher E/e′ ratio (β=0.059; adjusted P=0.014). CAC was measured at both year-15 examination and Y25 in 2449 individuals. Higher change in CAC score during follow-up was independently related to higher LV mass index in blacks (β=4.789; adjusted P<0.001), but not in whites (β=1.051; adjusted P=0.283).ConclusionsHigher CAC in middle age is associated with higher LV mass and volumes and worse LV diastolic function. Being free of CAC from young adulthood to middle age correlates to better LV function at middle age. Higher change in CAC score during follow-up is independently related to higher LV mass index in blacks.

  • Periatrial Fat Quality Predicts Atrial Fibrillation Ablation Outcome
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-06-01
    Luisa Ciuffo, Hieu Nguyen, Mateus Diniz Marques, Konstantinos N. Aronis, Bhradeev Sivasambu, Henrique D. de Vasconcelos, Susumu Tao, David D. Spragg, Joseph E. Marine, Ronald D. Berger, Joao A.C. Lima, Hugh Calkins, Hiroshi Ashikaga

    BackgroundPrevious studies showed that the quantity of the left atrial (LA) periatrial fat tissue predicts recurrence after catheter ablation of atrial fibrillation (AF). We hypothesized that the quality of the LA periatrial fat tissue, measured by the mean computed tomography attenuation, predicts recurrence after AF ablation independent of the quantity of the LA periatrial fat tissue.MethodsWe included 143 consecutive patients with drug-refractory AF referred for the first catheter ablation of AF (62.2±10 years, 40% nonparoxysmal AF). All participants had a preablation cardiac computed tomography. We measured the quantity of the LA periatrial fat tissue by the area (millimeter square) and the quality by the mean computed tomography attenuation (Hounsfield units) in a standard 4-chamber view.ResultsPatients with AF recurrence after ablation (n=57) had a significantly larger fat area (167.6 [interquartile range, 124.1–255] versus 145.4 [95.6–229.3] mm2; P=0.018) and a higher fat attenuation (−92.0±9.8 versus −96.5±9.4 Hounsfield units; P=0.006) than those without recurrence (controls). LA fat attenuation was correlated with LA fat volume and LA bipolar voltage by invasive mapping and was associated with AF recurrence after adjusting for clinical risk factors, including body mass index, AF type, LA dimension, and fat area (hazard ratio, 2.65; P=0.001).ConclusionsThe quality of the LA periatrial fat tissue is an independent predictor of recurrence after the first AF ablation. Assessment of LA periatrial fat attenuation can improve AF ablation outcomes by refining patient selection.

  • Diagnostic Accuracy of Advanced Imaging in Cardiac Sarcoidosis
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-06-01
    Sanjay Divakaran, Garrick C. Stewart, Neal K. Lakdawala, Robert F. Padera, Wunan Zhou, Akshay S. Desai, Michael M. Givertz, Mandeep R. Mehra, Raymond Y. Kwong, Sandeep S. Hedgire, Brian B. Ghoshhajra, Viviany R. Taqueti, Hicham Skali, Sharmila Dorbala, Ron Blankstein, Marcelo F. Di Carli

    BackgroundThe diagnostic yield of cardiac sarcoidosis (CS) by endomyocardial biopsy is limited. Fluorodeoxyglucose (FDG) positron emission tomography (PET) and cardiac magnetic resonance imaging (MRI) may facilitate noninvasive diagnosis, but the accuracy of this approach is not well defined. We aimed to correlate findings from FDG PET and cardiac MRI with histological findings from explanted hearts of patients who underwent cardiac transplantation.MethodsWe analyzed the explanted heart histology for all patients who underwent cardiac transplant at our center from April 2008 to July 2018 and had pretransplant FDG PET (n=18) or cardiac MRI (n=31). The likelihood of CS based on FDG PET or cardiac MRI was categorized in a blinded fashion using a previously published method.RESULTS:Using a CS probable cutoff for FDG PET resulted in a sensitivity of 100.0% (95% CI, 54.1%–100.0%) and a specificity of 33.3% (95% CI, 9.9%–65.1%). Three of the 9 CS probable by FDG PET cases were found to be arrhythmogenic cardiomyopathy. The test characteristics of cardiac MRI are more challenging to comment on using our data as there was only one confirmed case of CS on post-transplant histological assessment. Of the 8 CS highly probable or probable cases by cardiac MRI, 3 were found to be dilated cardiomyopathy, and 2 were found to be end-stage hypertrophic cardiomyopathy.ConclusionsFDG PET and cardiac MRI can help facilitate the diagnosis of CS in patients with advanced heart failure with a high degree of sensitivity but lower specificity.

  • Apparent Declining Prognostic Value of a Negative Stress Echocardiography Based on Regional Wall Motion Abnormalities in Patients With Normal Resting Left Ventricular Function Due to the Changing Referral Profile of the Population Under Study
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-06-01
    Lauro Cortigiani, Mădălina-Loredana Urluescu, Maico Coltelli, Clara Carpeggiani, Francesco Bovenzi, Eugenio Picano

    BackgroundCardiology guidelines identify the low-risk response during stress echocardiography as the absence of regional wall motion abnormalities.MethodsFrom 1983 to 2016, we enrolled 5817 patients (age 63±12 years; 2830 males) with suspected coronary artery disease, normal regional, and global left ventricular function at rest and during stress (exercise in 692, dipyridamole in 4291, and dobutamine in 834). Based on timing of enrollment, 4 groups were identified in chronological order of recruitment: years 1983 to 1989, group 1 (n=211); years 1990 to 1999, group 2 (n=1491); years 2000 to 2009, group 3 (n=3285); and years 2010 to 2016, group 4 (n=830).ResultsThere were 240 (4%) events (119 deaths and 121 infarctions) in the follow-up. At 1-year follow-up, the event rate was 0.5% (95% CI, 0.05–0.95), 1.5% (95% CI, −1.18 to 1.82), 1.9% (95% CI, 1.63–2.17), and 1.7% (95% CI, 1.01–2.39; χ2, 9.0; P=0.03) in groups 1 to 4, respectively. At multivariable Cox analysis, independent predictors of future events were age (hazard ratio (HR), 1.05; 95% CI, 1.04–1.07; P<0.0001), male sex (HR, 1.57; 95% CI, 1.20–2.04; P=0.001), diabetes mellitus (HR, 1.78; 95% CI, 1.34–2.37; P<0.0001), smoking habit (HR, 1.40; 95% CI, 1.05–1.85; P=0.02), and ongoing anti-ischemic therapy (HR, 1.50; 95% CI, 1.15–1.97; P=0.003)ConclusionsOver the past 3 decades, we observed a progressive decline in the prognostic value of a negative test based on regional wall motion abnormalities, likely reflecting both an increase in risk in patients, as well as a potential decrease in test performance due to concomitant anti-ischemic therapy.

  • Left Ventricular Flow Analysis
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-05-01
    Victoria M. Stoll, Aaron T. Hess, Christopher T. Rodgers, Malenka M. Bissell, Petter Dyverfeldt, Tino Ebbers, Saul G. Myerson, Carl-Johan Carlhäll, Stefan Neubauer

    Background:Cardiac remodeling, after a myocardial insult, often causes progression to heart failure. The relationship between alterations in left ventricular blood flow, including kinetic energy (KE), and remodeling is uncertain. We hypothesized that increasing derangements in left ventricular blood flow would relate to (1) conventional cardiac remodeling markers, (2) increased levels of biochemical remodeling markers, (3) altered cardiac energetics, and (4) worsening patient symptoms and functional capacity.MethodsThirty-four dilated cardiomyopathy patients, 30 ischemic cardiomyopathy patients, and 36 controls underwent magnetic resonance including 4-dimensional flow, BNP (brain-type natriuretic peptide) measurement, functional capacity assessment (6-minute walk test), and symptom quantification. A subgroup of dilated cardiomyopathy and control subjects underwent cardiac energetic assessment. Left ventricular flow was separated into 4 components: direct flow, retained inflow, delayed ejection flow, and residual volume. Average KE throughout the cardiac cycle was calculated.Results:Patients had reduced direct flow proportion and direct-flow average KE compared with controls (P<0.0001). The residual volume proportion and residual volume average KE were increased in patients (P<0.0001). Importantly, in a multiple linear regression model to predict the patient’s 6-minute walk test, the independent predictors were age (β=−0.3015; P=0.019) and direct-flow average KE (β=0.280, P=0.035; R2 model, 0.466, P=0.002). In contrast, neither ejection fraction nor left ventricular volumes were independently predictive.Conclusions:This study demonstrates an independent predictive relationship between the direct-flow average KE and a prognostic measure of functional capacity. Intracardiac 4-dimensional flow parameters are novel biomarkers in heart failure and may provide additive value in monitoring new therapies and predicting prognosis.

  • Left Ventricular Twist Is Augmented in Hypoxia by β1-Adrenergic–Dependent and β1-Adrenergic–Independent Factors, Without Evidence of Endocardial Dysfunction
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-05-01
    Alexandra M. Williams, Philip N. Ainslie, James D. Anholm, Chris Gasho, Prajan Subedi, Mike Stembridge

    Background:Left ventricular (LV) twist mechanics are augmented with both acute and chronic hypoxemia. Although the underlying mechanisms remain unknown, sympathetic activation and a direct effect of hypoxemia on the myocardium have been proposed, the latter of which may produce subendocardial dysfunction that is masked by larger subepicardial torque. This study therefore sought to (1) determine the individual and combined influences of β1-AR (β1-adrenergic receptor) stimulation and peripheral O2 saturation (Spo2) on LV twist in acute and chronic hypoxia and (2) elucidate whether endocardial versus epicardial mechanics respond differently to hypoxia.Methods:Twelve males (27±4 years) were tested near sea level in acute hypoxia (Spo2=82±4%) and following 3 to 6 days at 5050 m (high altitude; Spo2=83±3%). In both settings, participants received infusions of β1-AR blocker esmolol and volume-matched saline (double-blind, randomized). LV mechanics were assessed with 2-dimensional speckle-tracking echocardiography, and region-specific analysis to compare subendocardial and subepicardial mechanics.Results:At sea level, compared with baseline (14.8±3.0°) LV twist was reduced with esmolol (11.2±3.3°; P=0.007) and augmented during hypoxia (19.6±4.9°; P<0.001), whereas esmolol+hypoxia augmented twist compared with esmolol alone (16.5±3.3°; P<0.001). At 5050 m, LV twist was increased compared with sea level (19.5±5.4°; P=0.004), and reduced with esmolol (13.0±3.8°; P<0.001) and Spo2 normalization (12.8±3.4°; P<0.001). Moreover, esmolol+normalized Spo2 lowered twist further than esmolol alone (10.5±3.1°; P=0.036). There was no mechanics-derived evidence of endocardial dysfunction with hypoxia at sea level or high altitude.Conclusions:These findings suggest LV twist is augmented in hypoxia via β1-AR–dependent and β1-AR–independent mechanisms (eg, α1-AR stimulation), but does not appear to reflect endocardial dysfunction.

  • Association of Arsenic Exposure With Cardiac Geometry and Left Ventricular Function in Young Adults
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-05-01
    Gernot Pichler, Maria Grau-Perez, Maria Tellez-Plaza, Jason Umans, Lyle Best, Shelley Cole, Walter Goessler, Kevin Francesconi, Jonathan Newman, Josep Redon, Richard Devereux, Ana Navas-Acien

    Background:Arsenic exposure has been related to numerous adverse cardiovascular outcomes. The aim of this study was to investigate the cross-sectional and prospective association between arsenic exposure with echocardiographic measures of left ventricular (LV) geometry and functioning.Methods:A total of 1337 young adult participants free of diabetes mellitus and cardiovascular disease were recruited from the SHFS (Strong Heart Family Study). The sum of inorganic and methylated arsenic concentrations in urine (ΣAs) at baseline was used as a biomarker of arsenic exposure. LV geometry and functioning were assessed using transthoracic echocardiography at baseline and follow-up.Results:Mean follow-up was 5.6 years, and median (interquartile range) of ΣAs was 4.2 (2.8–6.9) µg/g creatinine. Increased arsenic exposure was associated with prevalent LV hypertrophy, with an odds ratio (95% CI) per a 2-fold increase in ΣAs of 1.47 (1.05–2.08) in all participants and of 1.58 (1.04–2.41) among prehypertensive or hypertensive individuals. Measures of LV geometry, including LV mass index, left atrial systolic diameter, interventricular septum, and LV posterior wall thickness, were positively and significantly related to arsenic exposure. Among measures of LV functioning, stroke volume, and ejection fraction were associated with arsenic exposure.Conclusions:Arsenic exposure was related to an increase in LV wall thickness and LV hypertrophy in young American Indians with a low burden of cardiovascular risk factors. The relationship was stronger in participants with prehypertension or hypertension, suggesting that potential cardiotoxic effects of arsenic might be more pronounced in individuals already undergoing cardiovascular adaptive mechanisms following elevated systemic blood pressure.

  • Myocardial Fibrosis in Classical Low-Flow, Low-Gradient Aortic Stenosis
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-05-01
    Vitor E.E. Rosa, Henrique B. Ribeiro, Roney O. Sampaio, Thamara C. Morais, Marcela E.E. Rosa, Lucas J.T. Pires, Marcelo L.C. Vieira, Wilson Mathias Jr, Carlos E. Rochitte, Antonio S.A.L. de Santis, Joao Ricardo C. Fernandes, Tarso A.D. Accorsi, Pablo M.A. Pomerantzeff, Josep Rodés-Cabau, Philippe Pibarot, Flavio Tarasoutchi

    BackgroundFew data exist on the degree of interstitial myocardial fibrosis in patients with classical low-flow, low-gradient aortic stenosis (LFLG-AS) and its association with left ventricular flow reserve (FR) on dobutamine stress echocardiography. This study sought to evaluate the diffuse interstitial fibrosis measured by T1 mapping cardiac magnetic resonance technique in LFLG-AS patients with and without FR.MethodsProspective study including 65 consecutive patients (41 LFLG-AS [mean age, 67.1±8.4 years; 83% men] and 24 high-gradient aortic stenosis used as controls) undergoing dobutamine stress echocardiography to assess FR and cardiac magnetic resonance to determine the extracellular volume (ECV) fraction of the myocardium, indexed ECV (iECV) to body surface area and late gadolinium enhancement.ResultsInterstitial myocardial fibrosis measured by iECV was higher in patients with LFLG-AS with and without FR as compared with high-gradient aortic stenosis (35.25±9.75 versus 32.93±11.00 versus 21.19±6.47 mL/m2, respectively; P<0.001). However, both ECV and iECV levels were similar between LFLG-AS patients with and without FR (P=0.950 and P=0.701, respectively). Also, FR did not correlate significantly with ECV (r=−0.16, P=0.31) or iECV (r=0.11, P=0.51). Late gadolinium enhancement mass was also similar in patients with versus without FR but lower in high-gradient aortic stenosis (13.3±10.2 versus 10.5±7.5 versus 4.8±5.9 g, respectively; P=0.018).ConclusionsPatients with LFLG-AS have higher ECV, iECV, and late gadolinium enhancement mass compared with high-gradient aortic stenosis. Moreover, among patients with LFLG-AS, the degree of myocardial fibrosis was similar in patients with versus those without FR. These findings suggest that diffuse myocardial fibrosis may not be the main factor responsible for the absence of FR in LFLG-AS patients.

  • Impaired Cardiovascular Magnetic Resonance–Derived Rapid Semiautomated Right Atrial Longitudinal Strain Is Associated With Decompensated Hemodynamics in Pulmonary Arterial Hypertension
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-05-01
    Shuang Leng, Yang Dong, Yang Wu, Xiaodan Zhao, Wen Ruan, Gangcheng Zhang, John C. Allen, Angela S. Koh, Ru-San Tan, James W. Yip, Ju Le Tan, Yucheng Chen, Liang Zhong

    BackgroundThe transition of right ventricle (RV) from a compensated to decompensated state contributes to survival in pulmonary arterial hypertension (PAH). This study investigates the significance of right atrial (RA) dysfunction on disease progression in PAH.MethodsEighty patients with PAH, including 58 with hemodynamically compensated RV function (PAH-C) and 22 with decompensated RV function (PAH-D), were compared with 80 age-matched and sex-matched normal controls. RA longitudinal strain and strain rate (SR) parameters corresponding to reservoir (total strain εs and strain rate SRs), conduit (passive strain εe and strain rate SRe), and booster pump (active strain εa and strain rate SRa) phases were derived by a rapid semiautomated method on cine cardiovascular magnetic resonance.ResultsIn PAH compared with controls, significantly reduced RA strains and SRs were observed. Among patients with PAH, PAH-D had significantly impaired RA strains and SRs compared with PAH-C. RA total strain and passive strain were the best parameters for differentiating PAH-D from PAH-C. Lower RA strain correlated with increased RA pressure (r=−0.57; P<0.0001), RV volume (r=−0.37; P=0.002) and biomarker (r=−0.53; P<0.0001), impaired RV function (r=0.46–0.72; P<0.0001), and lower exercise capacity (r=0.41; P<0.0001). Reduced RA strains were significantly associated with higher risk of clinical worsening in PAH. RA passive strain was the best predictor of a composite adverse event end point (Harrell’s C statistic,0.75; hazard ratio,0.84; P=0.019) compared with other conventional RA and RV functional measurements.ConclusionsRA phasic functions are impaired in PAH. Among patients with PAH, impaired RA strains reflect RV decompensation and higher risks and predict adverse clinical outcomes.Clinical Trial Registrationhttps://www.clinicaltrials.gov. Unique identifier: NCT02790918.

  • Noncontrast Magnetic Resonance Angiography for the Diagnosis of Peripheral Vascular Disease
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-05-01
    Armando Ugo Cavallo, Ioannis Koktzoglou, Robert R. Edelman, Robert Gilkeson, Georgeta Mihai, Taehoon Shin, Sanjay Rajagopalan

    Contrast-enhanced magnetic resonance angiography (MRA) provides excellent assessment of the peripheral arterial vasculature and is considered an important adjunctive diagnostic modality for the assessment of peripheral arterial disease. However, given the high prevalence of chronic kidney disease in patients with peripheral arterial disease, the association of gadolinium contrast media with nephrogenic systemic fibrosis, and recent concern with consequences of long-term deposition of gadolinium in the brain, there has been a renewed interest in noncontrast MRA approaches. Recent improvements in pulse sequences combined with instrumentation have facilitated the development of newer noncontrast MRA sequences that provide high spatial resolution, allowing the evaluation of distal (infrageniculate and pedal) vessels of importance in patients with critical limb ischemia. Further, many of these sequences are time efficient and versatile, allowing rapid evaluation of the entire lower extremity vasculature. In this comprehensive review, we outline historic techniques and compare these with newer approaches such as quiescent interval slice-selective MRA, 3-dimensional fast spin echo , and velocity-sensitive MRA that are emerging as an alternative to computed tomographic angiography or digital subtraction angiography for the evaluation of lower limb arteries in patients with peripheral arterial disease. Technical details and applications in clinical practice will be discussed.

  • Left Ventricular Twist Mechanics to Identify Left Ventricular Noncompaction in Childhood
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-04-12
    Jolanda Sabatino, Giovanni Di Salvo, Sylvia Krupickova, Alain Fraisse, Costantina Prota, Valentina Bucciarelli, Manjit Josen, Josefa Paredes, Domenico Sirico, Inga Voges, Ciro Indolfi, Sanjay Prasad, Piers Daubeney

    BackgroundLeft ventricular noncompaction cardiomyopathy (LVNC) is associated with poor clinical outcome in childhood. Standard diagnostic criteria are still controversial, especially in young patients. Recent studies in adults demonstrated that left ventricular (LV) twist is abnormal in LVNC, but it has not been investigated in pediatric patients to date. Our aim was to assess LV cardiac mechanics, LV twist, and the prevalence of rigid body rotation, using 2-dimensional speckle tracking echocardiography, in young patients with LVNC and LV hypertrabeculation.MethodsForty-seven children (age range: 0–18 years) were assessed for suspected LVNC. All patients underwent 2-dimensional speckle tracking echocardiography and cardiovascular magnetic resonance imaging at 1.5 Tesla (T). Twenty-three patients fulfilled the cardiovascular magnetic resonance imaging diagnostic criteria for LVNC (LVNC group), while the remaining 24 did not and were included in the LV hypertrabeculation group. Forty-seven age- and sex-matched healthy volunteers were used as controls.ResultsThe average LV twist was significantly reduced in LVNC compared with control and LV hypertrabeculation. Rigid body rotation was recognized in 13 (56%) children with LVNC and in 1 (4%) child with LV hypertrabeculation and a strong family history for LVNC. Multivariable analysis demonstrated that LV twist is an independent predictor of LVNC (P=0.006; coefficient=0.462). The receiver operating characteristics curve showed that LV twist had optimal predictive value to discriminate patients with LVNC (cutoff value <5.8°; sensitivity, 82%; specificity, 92%; area under the curve=0.914).ConclusionsLV twist has good predictive value in diagnosing LVNC in young patients. Our findings strongly support the routine use of 2-dimensional speckle tracking echocardiography in the evaluation of young patients with suspected LVNC.

  • Association of Echocardiographic Parameters of Right Ventricular Remodeling and Myocardial Performance With Modified Task Force Criteria in Adolescents With Arrhythmogenic Right Ventricular Cardiomyopathy
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-04-10
    Guido E. Pieles, Lars Grosse-Wortmann, Majeda Hader, Meena Fatah, Paweena Chungsomprasong, Cameron Slorach, Wei Hui, Chun-Po Steve Fan, Cedric Manlhiot, Luc Mertens, Robert Hamilton, Mark K. Friedberg

    BackgroundThe usefulness of echocardiographic indices, including those already used by modified Task Force Criteria (mTFC), and others such as strain imaging, to identify arrhythmogenic right ventricular cardiomyopathy (ARVC) in adolescence is not well established.MethodsEchocardiograms from 120 adolescents investigated for ARVC (13±4 years) were retrospectively analyzed. According to the mTFC, patients were classified into definite (n=38), borderline (n=39), or possible (n=43) ARVC. Results were compared with 35 healthy controls. mTFC echocardiographic parameters were analyzed, as well as comprehensive right ventricular (RV) and left ventricular assessment of function including parameters not included in mTFC such as pulsed-wave tissue Doppler and RV 2-dimensional speckle strain.ResultsmTFC parameters indexed for body surface area were significantly more abnormal in patients with possible, borderline, or definite ARVC compared with controls for parasternal long-axis view of the RV outflow tract. RV end-diastolic diameters were significantly larger in patients versus controls, a difference that increased with likelihood of ARVC. Left ventricular ejection fraction, tricuspid annular peak systolic excursion, and systolic and diastolic pulsed-wave tissue Doppler imaging indices were similar to controls for all groups. Average and segmental RV peak longitudinal systolic strain was significantly lower in patients with definite ARVC (−21±4%) and disease subgroups versus controls (−25±3%). Multivariable risk analysis showed that reduced RV strain was significantly associated with ARVC diagnosis and its likelihood (multivariable odds ratio [95% CI]=1.23 [1.1–1.37]; P<0.001) as was increased end-diastolic diameter at the apical third of the RV (multivariable odds ratio [95% CI]=1.51 [1.33–1.72]; P<0.001).ConclusionsmTFC echocardiographic criteria are significantly different between patients and controls and between the different diagnostic groups. However, in our cohort, current echocardiographic mTFC are not met by the majority of adolescent ARVC patients, particularly when indexed to body surface area. Measurement of RV apical dimensions and strain may increase the diagnostic yield of echocardiography for ARVC.

  • Morphology and Function of the Lymphatic Vasculature in Patients With a Fontan Circulation
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-04-04
    Sheyanth Mohanakumar, Niklas Telinius, Benjamin Kelly, Henrik Lauridsen, Donna Boedtkjer, Michael Pedersen, Marc de Leval, Vibeke Hjortdal

    Background:The Fontan procedure has revolutionized the treatment of univentricular hearts. However, it is associated with severe complications such as protein-losing enteropathy, plastic bronchitis, and peripheral edema that may involve the lymphatic circulation. We aimed to assess lymphatic function and morphology in patients with a univentricular circulation.Methods:The functional state of lymphatic vessels in the lower extremities of patients with a Fontan circulation (n=10) was investigated using the novel technique near-infrared fluorescence imaging and compared with an age-, sex-, and weight-matched control group of healthy volunteers (n=10). The lymphatic morphology was described using T2-weighted magnetic resonance imaging, and microvascular permeability was estimated by strain gauge plethysmography.Results:The Fontan patients had 17% lower lymphatic pumping pressure (50±3.1 mm Hg) compared with controls (60±2.8 mm Hg; P=0.0341) and a 62% higher contraction frequency (0.8±0.1 min−1) compared with the healthy controls (0.5±0.1 min−1; P=0.0432). Velocity by which the lymph is moved and refill time after manual emptying of the lymphatic vessels showed no differences between the 2 groups. The thoracic duct was elongated 10% (P=0.0409) and with an abnormal course in the Fontan patients compared with normal. No difference in microvascular permeability was found between the 2 groups.Conclusions:Patients with a Fontan circulation have an impaired lymphatic pumping capacity and morphologically changed thoracic duct. Our results indicate a challenged lymphatic vasculature in the Fontan circulation and may play a role in the pathogenesis of the complications that are seen in Fontan patients.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT03379805.

  • Predictors of Clinical Evolution in Prehypertrophic Fabry Disease
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-04-04
    Antonia Camporeale, Maurizio Pieroni, Federico Pieruzzi, Paola Lusardi, Silvia Pica, Marco Spada, Renzo Mignani, Alessandro Burlina, Francesco Bandera, Marco Guazzi, Francesca Graziani, Filippo Crea, Adreas Greiser, Sara Boveri, Federico Ambrogi, Massimo Lombardi

    Background:In prehypertrophic Fabry disease, low myocardial T1 values, reflecting sphingolipid storage, are associated with early structural and ECG changes. The correlations between T1 values and functional parameters have not been explored. Furthermore, the potential prognostic role of T1 in predicting disease worsening is still unknown.Methods:ECG, 2D echocardiography, cardiopulmonary test, and cardiac magnetic resonance were performed in 44 Fabry patients without left ventricular hypertrophy (35.7±14.5 years, 68.2% females). After a 12-month follow-up, clinical stability was evaluated using Fabry Stabilization Index.Results:At baseline, T1 values showed a negative correlation with left ventricular mass (r=−0.79; P<0.0001), maximum wall thickness (r=−0.79; P<0.0001), Sokolow-Lyon Index (r=−0.54; P<0.0001), left atrial volume (r=−0.49; P<0.0002), and Mainz Severity Score Index (r=−0.61; P<0.0001). No significant differences in systo-diastolic function and exercise capacity were observed comparing normal and low T1 Fabry patients. Arrhythmias were reported in 2 females with low T1 and late gadolinium enhancement. Five patients (40.0±12.4 years, 2 females) showed clinical worsening (Fabry Stabilization Index >20%) at follow-up. Higher left ventricular wall thickness (odds ratio, 2.61; CI, 1.04–6.57; P=0.04), left atrial volume (odds ratio, 1.24; CI, 1.02–1.51; P=0.03), and lower T1 values (odds ratio, 0.98; CI, 0.96–0.99; P=0.03) at baseline were independently associated with clinical worsening at follow-up.Conclusions:In prehypertrophic Fabry disease, low T1 values correlate with early electrocardiographic, morphological cardiac changes, and worsening of global disease severity but are not associated with functional abnormalities. The presence of low T1 values is a risk factor for disease worsening, thus representing a potential new tool in prognostic stratification and therapeutic approach.

  • Imaging the Lymphatic System in Fontan Patients
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-04-04
    Floris E.A. Udink ten Cate, Eric T.T.L. Tjwa

    See Article by Mohanakumar et al The Fontan operation has tremendously improved survival of patients with univentricular hearts during the past 2 decades.1,2 It should be acknowledged that, in the early days of Fontan palliation, our focus was primarily on surgical and perioperative aspects of the Fontan operation, in an attempt to decrease morbidity and mortality related to the operation itself.1,2 However, that focus has now been modified and is shifted toward the long-term outcome perspective of patients with a Fontan circulation, as it has become clear that the Fontan circulation affects most organs in the human body, particularly the liver, with low cardiac output and chronically elevated systemic venous pressure likely being the substrates for development of major adverse events.3,4 Therefore, the identification of modifiable risk factors to optimize Fontan hemodynamics, to prevent or slow down the deterioration of organ function, and to develop new therapeutic strategies has been given a high research priority in recent literature.2–4 The lymphatic system might be such a risk factor, predisposing Fontan patients with maladaptive lymphatic remodeling to lymphedema, plastic bronchitis, and protein-losing enteropathy.4–6 Until recently, the lymphatic system has been difficult to investigate because a simple and reliable imaging method was lacking.5 However, recent developments in magnetic resonance imaging (MRI) techniques make it possible to delineate the central lymphatic system in Fontan patients with good spatial en temporal resolution.5,7,8 This has paved the way for opening the lymphatic black box. In this context, the work of Mohanakumar et al9 in this issue of Circulation: Cardiovascular Imaging is an important addition to our understanding of the lymphatic system in both asymptomatic and symptomatic Fontan patients. The authors used state-of-the-art imaging modalities to carefully delineate the lymphatic system of a well-characterized group of Fontan patients and compared the results with healthy age- and sex-matched control subjects. Blinded to clinical and hemodynamic data, each participant underwent T2-weighted noncontrast MRI lymphangiography to examine the lymphatic anatomy of the neck, entire chest, including the thoracic duct (TD), abdomen, and legs. T2-weighted MRI is noninvasive and is able to demonstrate alterations in lymphatic structures, such as lymphatic collateralization, lymphangiectasias (dilatation of lymphatic vessels), dilatation of the cisterna chyli or TD, and the presence of fluid accumulation in tissues or body cavities.5–9 An important disadvantage of T2-weighted MRI is that it is a static imaging modality, meaning that no dynamic information on lymph flow is gathered during the study.5,7,8 Therefore, Mohanakumar et al9 also investigated the functional state of the lymphatic vessels using near-infrared fluorescence imaging, which is a novel technique that allows both anatomic delineation of lymphatic structures and real-time visualization of lymph flow. Furthermore, the microvascular permeability of lymphatic vessels in the lower extremities was estimated by strain gauge plethysmography, thus providing us with a detailed exploration of the lymphatic system in Fontan patients. The lymphatic system is distributed throughout most of the human body and runs parallel to the blood vascular system.10 Because the blood microvasculature is permeable to water and proteins, ≈8 to 10 L of blood plasma extravasates every day into surrounding tissue.10,11 This physiological process is of paramount importance for normal functioning of the extracellular matrix and the cellular components of our tissues.11,12 This interstitial fluid, or lymph, is transported back to the systemic circulation. The lymphatic vasculature system facilitates this transport of lymph through an extensive network of highly sophisticated lymphatic vessels that are interconnected with lymph nodes, central lymphatic ducts, the spleen, and Peyer’s patches in the small intestine and ultimately enters the systemic circulation through the TD in most subjects.10–12 Lymphatic vessels are organized as a vessel tree, where fluid from the tissue enters the most distal part of the lymphatic system, the lymphatic capillaries, or initial lymphatics.10 These lymphatic vessels are blind-ending and composed of a single layer of endothelial cells.10 Initial lymphatics pass the fluid to collecting lymphatics. Collecting lymphatics are larger vessels lined with endothelium and surrounded by a muscle layer.10 Action potentials in the smooth muscle layer of the collecting lymphatic vessels elicit phasic contractions, resulting in forward flow of lymph through the lymphatic system.10–12 Moreover, collecting lymphatics comprised serially arranged structural and functional units called lymphangions.10–12 A lymphangion is the segment of a collecting lymphatic vessel between 2 adjacent valves. These intraluminal valves prevent backflow of lymph within the lymphatic network, further underscoring the importance of a normal functioning lymphatic network.10–12 The lymphatic system not only is involved in maintaining a normal interstitial fluid balance and protein concentration but also plays an important role in the transport of lipids from the gastrointestinal tract, removal of substances that arise because of metabolism or cell death, and in optimizing our immunity.10–12 Not surprisingly, there is accumulating evidence to suggest that a disrupted lymphatic system, not related to primary genetic disorders, contributes to a variety of disorders, such as metabolic syndrome, heart failure, cancer, and inflammatory bowel disease.10,12 Tissue inflammation is associated with increased permeability of the blood capillaries and reduced lymphatic pumping, which may result in local edema and disruption of immune homeostasis.10,12 Poor drainage leads to impaired transport of immune cells, aggravating local tissue dysfunction. In view of this, it seems relevant to note that the Fontan circulation is a state of chronic heart failure associated with augmented systemic inflammation and increased neurohumoral activation. Therefore, it is conceivable that lymphatic dysfunction contributes in some part to the deterioration of organ function in Fontan patients. A small number of research groups have recently begun to unravel the structural and functional alterations of the lymphatic system in Fontan patients.5–9 The lymphatic system in Fontan patients is chronically challenged, not only because of the increased production of interstitial fluid that the lymphatic vessels have to remove to maintain a normal tissue-fluid balance, but also secondary to a significant elevation in afterload (systemic venous pressure), potentially limiting the transport capacity of the lymphatic system as a whole.5–9 This may predispose Fontan patients to maladaptive remodeling of the central lymphatics, subsequently contributing to the development of lymphedema, plastic bronchitis, and possibly protein-losing enteropathy.5–9 Dilation and tortuosity of the TD, lymphatic collaterals, lymphangiectasia, and leakage of lymph in surrounding tissue are the most common lymphatic abnormalities seen in Fontan patients.5,9 In addition, these lymphatic abnormalities, which are not disease specific, have also been observed in infants with single ventricle physiology following a superior cavopulmonary connection, suggesting that maladaptive remodeling of the central lymphatics may already be present before the Fontan operation in a subset of these patients.5 The measurement of the TD diameter deserves special attention. The TD is the largest lymphatic duct and receives lymph from 80% to 90% of the body.10–12 It originates from the cisterna chyli, which is typically located at the level of L1 and L2 and enters the thoracic cavity through the aortic hiatus.12–14 In most humans, the TD ascends between the aorta and the azygos vein, crosses the mediastinum posteriorly, and drains into the junction of the left subclavian and left internal jugular veins. Dilation of the TD seems a common feature in patients with a dysfunctional lymphatic system.7,8,13 Notably, the TD is a dynamic vessel; with higher lymph production, a local stenosis, or a significant elevation of the afterload, its diameter will increase. The average diameter of the TD in healthy adults is normally between 2.5 and 4 mm, and it may increase to 9 to 10 mm in patients with portal hypertension, liver cirrhosis, or heart failure.7,8,13 Therefore, measurement of the TD diameter in Fontan patients may have important clinical implications. However, the interpretation of the TD diameter should be viewed in the context of specific limitations. First, the anatomy and course of the TD in humans is highly variable.12–14 Second, lymphatic abnormalities of unknown relevance may also be present in asymptomatic healthy subjects, as was observed in the present study.9 Third, the diameter of the TD is influenced by the circadian cycle and increases significantly after a (fatty) meal,7 suggesting that a standardized fluid/meal protocol is required for a reproducible assessment of the central lymphatic system. And finally, the TD imaging quality of T2-weighted noncontrast MRI may be limited in some patients. These considerations should be taken into account before a clinically meaningful distinction between a challenged but adapted, or a diseased TD in Fontan patients can be made. Facing these limitations, Mohanakumar et al9 are to be congratulated on overcoming considerable challenges involved in unraveling the morphology and function of the lymphatic system in Fontan patients. To eliminate any circadian influence, the tests were conducted before midday and the subjects were instructed to refrain from heavy physical exercise and alcoholic beverages 12 hours before testing. Intake of beverages and food during the tests was not allowed.9 Furthermore, to quantify the degree of TD tortuosity, the authors calculated the relative length of the TD from T2-weighted noncontrast MRI images. They showed that this measure of TD tortuosity was easy to obtain and highly reproducible. Although the TD diameter was not significantly different between Fontan patients and healthy controls, the degree of TD tortuosity was significantly increased in Fontan patients. Importantly, TD tortuosity seems a common and potentially distinctive feature of the lymphatic system in Fontan. Whether the TD tortuosity index is preload independent remains to be determined. Moreover, Fontan patients had 17% lower lymphatic pumping pressure and a 62% higher contraction frequency compared with healthy controls.9 These findings suggest that lymphatic disease in Fontan patients is characterized not only by alterations in TD morphology but also by impairment of the lymphatic pumping capacity. Another important finding of the present study is that lymphedema surrounding the liver was observed in most Fontan patients. Liver disease, ranging from mild fibrosis to severe cirrhosis and hepatocellular carcinoma, is increasingly being recognized in Fontan patients.15,16 Although risk factors for the development of Fontan-associated liver disease are currently being explored, the pathogenesis remains largely unknown and seems likely to be multifactorial. It should be acknowledged that the liver produces a large amount of lymph; 25% to 50% of the lymph flowing through the TD originates from the liver. Lymph production arises primarily from the hepatic sinusoids and is proportional to the hydrostatic pressure within the sinusoidal microcirculation of the liver. Interestingly, sinusoidal dilation due to hepatic congestion is a common histopathologic finding in patients with Fontan-associated liver disease.15,16 Moreover, the interstitial fluid content is increased in the liver and surrounding tissue in patients with cirrhosis and portal hypertension, which may give rise to local lymphedema, TD dilation, and ultimately ascites when the transport capacity of the lymphatic system fails.17 Consequently, poor drainage of lymph may further aggravate liver dysfunction, tissue inflammation, fibrosis, and lymphangiogenesis.17,18 Although it is tempting to conclude that a challenged lymphatic system in patients following the Fontan procedure directly contributes to the development and progression of Fontan-associated liver disease, the liver status of the patients in this study was not assessed. Going forward, this important observation warrants further exploration and should be used to guide larger prospective studies. Although the fundamental question—how do we define a normal and adapted lymphatic system in Fontan survivors?—has not been answered yet, there can be no question about the importance of noninvasive imaging techniques in the evaluation of the lymphatics in Fontan patients. The ultimate goal of research is to identify Fontan patients at highest risk for poor outcome and to provide novel targets for treatment. The degree of TD tortuosity may ultimately prove to be a helpful measure in this context. Furthermore, this study highlights the need for continued clinical research of the lymphatic system in larger cohorts of Fontan survivors. Future studies should focus on the serial assessment of the lymphatic system in relation to specific patient characteristics and complications such as Fontan-associated liver disease, plastic bronchitis, and protein-losing enteropathy. Nevertheless, we should keep in mind that a normal functioning Fontan circulation is still markedly abnormal and that the lymphatic system seems to play an important role to compensate for its abnormality. None. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

  • Mapping Phenotype Development in Fabry Disease
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-04-04
    João B. Augusto, James C. Moon

    See Article by Camporeale et al Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death and heart failure. Within the HCM, clinical spectrum mimics genocopies and phenocopies such as amyloid and Fabry disease (FD) that it is important to detect as there may be specific available therapies.1 This statement highlights that modern medicine lacks disease-modifying therapy for typical sarcomeric HCM. HCM is genetically and phenotypically complex.2 Our understanding about how hundreds of mutations in 11 genes lead to overt disease, morbidity and mortality is frustrated by our poor understanding of the underlying pathophysiology and stages of cardiomyopathy development. This itself is based on difficulties in “reading out” signals in vivo using imaging and other techniques to elucidate processes activated in the myocardium, confounding drug development. Since the days of William Osler, it has been highlighted that rare diseases and cleaner phenotypes may permit pattern recognition clouded in more complex, typical disease. These may still use the same basic limited portfolio of cellular clockwork and mechanisms; for example, Anderson FD and amyloid cause left ventricular hypertrophy (LVH), one starting with intracellular sphingolipid storage3 and the other with extracellular protein deposition.4 Like sarcomeric HCM, however, they both may lead to changes in cardiomyocytes, fibroblasts, endothelial cells, and extracellular space.5 Societal endeavor and medicine in particular are driven by technological advances. Several disease mechanisms in HCM have been unveiled by the technology of cardiovascular magnetic resonance. Scar imaging by means of late gadolinium enhancement has allowed the acknowledgment of different scar patterns in HCM, amyloidosis, and FD,6–8 all potentially late disease features. But by using a different technique, T1 mapping, an unexpected finding is built on in this issue of Circulation: Cardiovascular Imaging, by Camporeale et al.9 The HCM genocopy FD results in a measurably low native (noncontrast) T1 in the myocardium of FD,10 and around half of subjects with a pathogenic gene mutation for FD have T1 lowering, even before LVH occurs.11 Remarkably, it appears that T1 mapping provides a “read-out” of the initial disease insult in FD—myocyte lipid storage. This signal is distinct from that in amyloid7 and near unique—only FD and iron overload substantially lower myocardial T1,10 although athletic adaptation can reduce T1 modestly. Its presence when combined with other assessments permits staging of established disease.12 Here, Camporeale et al9 address early disease. Focusing on the prehypertrophic stage, they conducted a prospective observational study of 44 LVH-negative FD patients to investigate the associations of low T1 with baseline cardiac function, exercise capacity, and cardiac arrhythmias, as well as interval change over 12 months. The authors show that low T1 was found in 59% of LVH-negative FD patients, in line with previous reports.11 T1 values inversely correlated with left ventricular mass/left ventricular maximum wall thickness and left atrial volume. Patients with low T1 values also had more electrocardiographic changes, particularly repolarization abnormalities and increased voltages. Functional status as assessed by the Mainz Severity Score Index was also significantly worse in patients with low T1. These associations highlight low myocardial T1 as an early phenotype marker not only for cardiac but also for systemic FD. Even in a clean monogenic disease such as FD, there was phenotypic heterogeneity. Low T1 was more prevalent in classical mutations, and there was sex dimorphism12 with low T1 being more prevalent in males and late gadolinium enhancement without LVH only occurring in females. Interestingly, however, both low and normal T1 groups showed markedly reduced functional capacity on cardiopulmonary exercise testing, suggesting that early limitation is not related to myocardial storage. This earlier, systemic phenotype may be musculoskeletal, inflammatory, neurological, endothelial, or indeed more complex, involving higher cortical function and motivation. Inflammatory pathways seem activated in myocardial FD once late gadolinium enhancement is present,13 but systemic inflammation may start earlier. Abnormal coronary microvascular function is recognized in FD patients with LVH,14 but whether this starts before LVH or T1 lowering (ie, myocyte storage) is currently unknown, although likely as endothelial cell storage appears more dynamic than terminally differentiated myocyte storage. Nevertheless, a low myocardial T1 mapping predicted clinical worsening at 12-month follow-up (as did left ventricular maximum wall thickness and left atrial volume) highlighting the links of myocardial involvement to systemic FD multi-organ involvement. How could we take these data further? To be able to measure the earliest steps of phenotype evolution before LVH is an opportunity. Sarcomeric HCM mutations have variable penetrance making the identification of early changes and therefore potential therapeutic targets harder. Here, in FD, a cohort likely to be about to develop LVH can be recognized with the potential to identify early biomarkers and key pathways for FD, with insights transferable to more complex diseases that may lead to the development of Precision Medicines. Within FD, the typical LVH-negative patient is currently untreated. Where there is a low T1 (storage), particularly with ECG changes (conduction disease) or late gadolinium enhancement/troponin elevation (inflammation), it is conceivable that therapy could switch disease off before the activation of potentially self-sustaining hypertrophic pathways. On the other hand, patients without storage may represent a stable, disease free, nonprogressing phenotype, confidently requiring no therapy. Clinical trials testing these hypotheses seem worthwhile. The authors Camporeale et al9 should be congratulated on their study and the potential insights it and other similar studies may provide, partly for the rare disease under investigation, but also for the transferability of insights into more prevalent conditions. Dr Moon is PI on an investigator-led grant from Sanofi Genzyme and has received honoraria from Sanofi Genzyme and Shire-Takeda. The other author reports no conflicts. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

  • Glycemic Markers and Subclinical Cardiovascular Disease: The Jackson Heart Study
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-03-18
    Justin B. Echouffo-Tcheugui, Haiying Chen, Rita R. Kalyani, Mario Sims, Sean Simpson, Valery S. Effoe, Adolfo Correa, Alain G. Bertoni, Sherita H. Golden

    BackgroundWe investigated the associations of glycemic markers (HbA1C [hemoglobin A1C], fasting plasma glucose, and insulin resistance—homeostasis model assessment of insulin resistance) with subclinical cardiovascular disease (CVD) among blacks.MethodsWe included 4303 community-dwelling blacks (64% women; mean age, 54.5 years) without prevalent CVD. Subclinical CVD was defined as ≥1 of the following: any coronary artery calcification (CAC), elevated carotid intima-media thickness (cIMT), left ventricular (LV) hypertrophy, LV ejection fraction <50%, and peripheral artery disease (ankle-brachial index, <0.90). Estimates of cross-sectional associations of glycemic markers (fasting plasma glucose, HbA1C, and homeostasis model assessment of insulin resistance) with subclinical CVD measures were adjusted for traditional CVD risk factors.ResultsEach 1% increment in HbA1C was associated with higher odds of CAC, abnormal cIMT, and subclinical CVD (all P <0.001). Adjusted mean values of LV mass (LVM), LVM index, relative wall thickness, CAC, and cIMT were increasingly abnormal with worsening HbA1C categories (all P<0.05). Each 10-mg/dL increase in fasting plasma glucose was associated with higher odds of LV hypertrophy, CAC, abnormal cIMT, and subclinical CVD (all P <0.005). Adjusted mean values of LVM, LVM index, relative wall thickness, CAC, ankle-brachial index, and cIMT were more abnormal across categories of worsening fasting plasma glucose (all P <0.05). Each unit increment in log-transformed homeostasis model assessment of insulin resistance conferred a higher odd of having LV hypertrophy (P<0.01). Across quartiles of homeostasis model assessment of insulin resistance, we observed progressively abnormal adjusted mean values of LVM, LVM index, relative wall thickness, and ankle-brachial index (all P <0.01).ConclusionsAmong blacks, glycemic markers were differentially associated with various measures of subclinical CVD.

  • Prognostic Implications of Right Ventricular Free Wall Longitudinal Strain in Patients With Significant Functional Tricuspid Regurgitation
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-03-18
    Edgard A. Prihadi, Pieter van der Bijl, Marlieke Dietz, Rachid Abou, E. Mara Vollema, Nina Ajmone Marsan, Victoria Delgado, Jeroen J. Bax

    BackgroundIn patients with significant functional tricuspid regurgitation, timely detection of right ventricular (RV) dysfunction with conventional 2-dimensional echocardiography is challenging, whereas speckle-tracking echocardiography RV free wall longitudinal strain has been proposed as better prognosticator. We evaluated the prevalence and prognostic value of impaired RV free wall longitudinal strain in patients with significant functional tricuspid regurgitation, in comparison with tricuspid annular plane systolic excursion (TAPSE) and fractional area change (FAC).MethodsEight hundred ninety-six patients (51.3% men, 71 years [62–78 years]) with significant functional tricuspid regurgitation were divided according to the presence of RV dysfunction (defined as TAPSE <17 mm, FAC <35%, and RV free wall longitudinal strain >−23%) and were followed for the occurrence of all-cause mortality.ResultsRV free wall longitudinal strain identified the highest percentage of RV dysfunction (84.9%), in comparison to FAC (48.5%) and TAPSE (71.7%). During a median follow-up of 2.8 years (1.3–5.4 years), 443 (49.4%) patients died. Compared with survivors, nonsurvivors showed worse RV systolic dysfunction (FAC=36.5±12.7% versus 33.9±11.8%, P=0.001; TAPSE=15.4±5.0 versus 14.0±4.5 mm, P<0.001; RV free wall longitudinal strain=−15.9±7.5% versus −12.9±6.8%, P<0.001). Cumulative event-free survival was significantly worse in patients with decreased FAC, decreased TAPSE, and impaired RV free wall longitudinal strain. On multivariate analysis, RV free wall longitudinal strain was independently associated with all-cause mortality and incremental to FAC and TAPSE.ConclusionsIn significant tricuspid regurgitation, impaired RV free wall longitudinal strain identifies higher rates of RV dysfunction and is associated with worse outcome beyond conventional echocardiographic parameters of RV systolic function.

  • Concurrent Molecular Magnetic Resonance Imaging of Inflammatory Activity and Extracellular Matrix Degradation for the Prediction of Aneurysm Rupture
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-03-15
    Julia Brangsch, Carolin Reimann, Jan O. Kaufmann, Lisa C. Adams, David C. Onthank, Christa Thöne-Reineke, Simon P. Robinson, Rebecca Buchholz, Uwe Karst, Rene M. Botnar, Bernd Hamm, Marcus R. Makowski

    Background:Molecular magnetic resonance imaging is a promising modality for the characterization of abdominal aortic aneurysms (AAAs). The combination of different molecular imaging biomarkers may improve the assessment of the risk of rupture. This study investigates the feasibility of imaging inflammatory activity and extracellular matrix degradation by concurrent dual-probe molecular magnetic resonance imaging in an AAA mouse model.Methods:Osmotic minipumps with a continuous infusion of Ang II (angiotensin II; 1000 ng/[kg·min]) to induce AAAs were implanted in apolipoprotein-deficient mice (N=58). Animals were assigned to 2 groups. In group 1 (longitudinal group, n=13), imaging was performed once after 1 week with a clinical dose of a macrophage-specific iron oxide–based probe (ferumoxytol, 4 mgFe/kg, surrogate marker for inflammatory activity) and an elastin-specific gadolinium-based probe (0.2 mmol/kg, surrogate marker for extracellular matrix degradation). Animals were then monitored with death as end point. In group 2 (week-by-week-group), imaging with both probes was performed after 1, 2, 3, and 4 weeks (n=9 per group). Both probes were evaluated in 1 magnetic resonance session.Results:The combined assessment of inflammatory activity and extracellular matrix degradation was the strongest predictor of AAA rupture (sensitivity 100%; specificity 89%; area under the curve, 0.99). Information from each single probe alone resulted in lower predictive accuracy. In vivo measurements for the elastin- and iron oxide–probe were in good agreement with ex vivo histopathology (Prussian blue-stain: R2=0.96, P<0.001; Elastica van Giesson stain: R2=0.79, P<0.001). Contrast-to-noise ratio measurements for the iron oxide and elastin-probe were in good agreement with inductively coupled mass spectroscopy (R2=0.88, R2=0.75, P<0.001) and laser ablation coupled to inductively coupled plasma–mass spectrometry.Conclusions:This study demonstrates the potential of the concurrent assessment of inflammatory activity and extracellular matrix degradation by dual-probe molecular magnetic resonance imaging in an AAA mouse model. Based on the combined information from both molecular probes, the rupture of AAAs could reliably be predicted.

  • Imaging Biomarkers for Abdominal Aortic Aneurysms
    Circ. Cardiovasc. Imaging (IF 5.813) Pub Date : 2019-03-15
    Rachael O. Forsythe, David E. Newby

    See Article by Brangsch et al In a recent international survey of vascular surgeons,1 the discovery of new tests to predict and to identify fast-growing abdominal aortic aneurysm (AAA) was seen as a top research priority. Indeed, various international guidelines have also highlighted this as an important knowledge gap that needs to be addressed.2,3 Such innovation would allow better targeted surveillance and preemptive surgery, which today relies almost solely on the overly simplistic dichotomous threshold of the maximum anteroposterior diameter of the AAA. It is against this backdrop that Brangsch et al4 report their novel imaging approach in the current edition of the Journal. The authors use a murine model to address one of the most pertinent questions in AAA research—how can we more accurately characterize the risk of aneurysm rupture? Brangsch et al4 have therefore offered us an interesting preclinical exploration into this topic, and their article has a number of important strengths. The search for a more accurate prediction of aneurysm disease progression has gathered pace in recent times. The acknowledgment of staccato growth in AAA5 is mitigated by our lack of understanding as to the reasons why aneurysms do not grow predictably, and why some may rupture at small diameters (even while under surveillance), whereas many aneurysms reach a large size but never rupture. However, although we may not fully understand the biological reasons behind these phenomena, we are becoming increasingly able to evaluate it. The use of novel molecular and cellular imaging is flourishing in cardiovascular research and has recently shown great promise in aneurysm disease. We6,7 and others8,9 have reported the use of imaging biomarkers to predict future aneurysm disease progression. As with many novel approaches, the question remains—where is the clinical relevance for such an expensive technique? Surely, in a world with a declining incidence of AAA disease, does this remain a priority? On the contrary—while the global incidence of AAA disease is indeed declining and the aneurysm-associated mortality has been reduced by the establishment of successful screening programs in many countries,10 there is a stubbornly high mortality associated with those aneurysms that do go on to rupture and there remains a lack of consensus around the world on whether, when, and how to treat patients with AAA.11,12 It would therefore benefit patients and healthcare providers to understand and to predict disease progression more fully at an individual patient level. Moreover, the use of molecular and cellular imaging techniques has the potential to provide noninvasive serial assessments of the vasculature for use in interventional trials—providing early and measurable surrogate end points for clinical events that would otherwise take many months or years to manifest or cause devastating clinical sequelae. For example, cellular imaging techniques using magnetic resonance imaging have previously been used to evaluate the change in inflammation as a response to statin therapy in patients with carotid artery disease,13 demonstrating a reduction in macrophage-mediated inflammation with the use of high dose statin therapy for 3 months. And so, this present study addresses a number of key issues pertaining to the assessment of aneurysm biology and its use beyond the preclinical arena. To date, the use of molecular and cellular imaging in aneurysm research has been limited to evaluating a single biomarker in clinical studies. However, aneurysm disease is in fact a multifactorial milieu of pathobiological activity, and this study explores 2 different—albeit closely interlinked—biological processes contemporaneously. Macrophage-mediated inflammation and extracellular matrix degradation are 2 key processes in aneurysm pathobiology, and their simultaneous evaluation has not previously been reported. This is a key strength of the study. The authors use a clinically validated imaging probe to evaluate macrophage-mediated inflammation—ultrasmall superparamagnetic particles of iron oxide (in this case, ferumoxytol). In clinical studies of AAA, ultrasmall superparamagnetic particles of iron oxide–enhanced magnetic resonance imaging has been shown to track active macrophages14 and to predict future aneurysm growth6,15,16 and the need for rupture or repair.6,16 In addition, the gadolinium-based elastin-specific probe, ESMA, which evaluates elastin degradation, has been evaluated in preclinical studies17,18 and shows great promise. However, by combining these 2 probes in the same sitting, the whole is greater than the sum of its parts and this is reflected in the results. In their longitudinal cohort study, magnetic resonance imaging with ultrasmall superparamagnetic particles of iron oxide or ESMA predicted aneurysm rupture with high sensitivity and specificity when each agent was used alone (sensitivity 80%, 80%; specificity 89%, 78%, respectively). However, when used in combination, these markers appeared to add incremental value and predicted events with near perfect accuracy: 100% sensitivity and 89% specificity. This suggests that macrophage-mediated inflammation and elastin breakdown in isolation or combination mediate nearly all the rupture events. A further strength of this study is the use of repeated imaging over 4 weeks of aneurysm development to chronicle the changes in the vasculature. This is one of the great advantages of imaging biomarkers—serial measurements of biological activity can be obtained. The authors observed that the early stage of AAA development was characterized by elastic fiber dissection, intramural hematoma, and dilatation of the aortic wall, followed by an increase in macrophage activity and further dilatation. In the later stages, there was intense remodeling at sites of rupture. To provide further validation of their findings, the authors compared in vivo markers of biological activity with ex vivo histological findings. They demonstrated the ability to characterize temporal changes of the vasculature in great detail. Importantly, the authors were able to demonstrate that there was no confounding effect from using the 2 probes when used simultaneously and performed competition experiments to verify the binding specificity of ESMA. This is a key step in the development of dual probe imaging. The major limitation of this study is the use of an inherently imperfect animal model of aneurysm disease. While the angiotensin II–infused apolipoprotein E–deficient mouse is one of the commonest models of human aneurysm disease, its limitations are well recognized. The mice typically form aneurysms in the suprarenal aorta, whereas 80% of human AAA are infrarenal. In addition, the animals tend to form aneurysms as a consequence of hypertension-induced aortic dissection and intramural hematoma, whereas the vast majority of AAA disease in humans is unrelated to dissection or intramural hematoma. Moreover, the pathogenesis of human disease is dominated by the combination of smoking and hypertension, with smoking being the strongest modifiable risk factor for disease progression. Nevertheless, the appeal of the article by Brangsch et al is that the authors have taken one step further and proven that it is mechanistically possible to evaluate more than one biological process at the same time using molecular magnetic resonance imaging. They have provided evidence of the independent value of the 2 imaging probes, but importantly, the improvement in rupture prediction when the assessment of macrophage-mediated inflammation and extracellular matrix degradation are combined. The ability to predict accurately an individual aneurysm’s future disease activity would be invaluable on many levels—surveillance programs could be tailored to an individual patient, intervention thresholds could be adapted according to biological as well as clinical risk, and difficult decision-making could be guided by integrated assessment of all known risk factors. However, no molecular or cellular imaging biomarker has to date given us the whole answer, but certainly we should be looking toward dual or multiprobe imaging to assess the various disease processes that interlink in human aortic aneurysm disease more comprehensively. With studies like these, we will hopefully soon see the development of imaging approaches that will predict disease progression and help us avoid the often devastating and fatal consequences of AAA rupture. The authors are supported by the British Heart Foundation (CH/09/002; RE/18/5/34216), Wellcome Trust (WT103782AIA), and Medical Research Council (11/20/03). The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

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上海纽约大学William Glover