Cardiovascular Magnetic Resonance Imaging in Patients With Ibrutinib-Associated Cardiotoxicity.

Importance: Ibrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown. Objective: To assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity. Design, Setting, and Participants: This cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry. Exposures: Ibrutinib treatment for cancer control. Main Outcomes and Measures: The primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk-matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE. Results: Overall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P < .001, P = .01, and P < .001, respectively, pre- vs post-ibrutinib treatment). Native T12SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P < .001). Over a median follow-up of 19 months, 13 (39.4%) experienced MACE. In multivariable models inclusive of traditional CVD risk factors, LGE (hazard ratio [HR], 4.9; P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE. Conclusions and Relevance: In this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.

Nonsustained Ventricular Tachycardia Is Independently Associated With Sustained Ventricular Arrhythmias in Nonischemic Dilated Cardiomyopathy.

BACKGROUND: Spontaneous nonsustained ventricular tachycardia (NSVT) on Holter, VT inducibility during electrophysiology study, and late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) have been associated with sustained ventricular arrhythmias (SVAs) in nonischemic dilated cardiomyopathy (DCM). This study aimed to analyze whether these parameters carry independent prognostic value for spontaneous SVA in DCM. METHODS: Between 2011 and 2018, patients with the DCM clinical spectrum and documented SVA, suspected SVA, or considered to be at intermediate or high risk for SVA were enrolled in the prospective Leiden Nonischemic Cardiomyopathy Study. Patients underwent a comprehensive evaluation including 24-hour Holter, LGE-CMR, and electrophysiology study. Holters were assessed for the presence of NSVT (≥3 beats; rate, ≥120 bpm; lasting <30 s) and NSVT characteristics (coupling interval, duration, cycle length, morphology, regularity). Patients were followed at 6 to 12 monthly intervals. RESULTS: Of all 115 patients (age, 59±12 years; 77% men; left ventricular ejection fraction, 33±13%; history of SVA, 36%; LGE in 63%; median LGE mass, 13 g; interquartile range, 8-23 g), 62 (54%) had NSVT on Holter, and sustained monomorphic VT was inducible in 34 of 114 patients (30%). NSVT was not associated with LGE on CMR or VT inducibility during electrophysiology study nor were its features (all P>0.05). During 4.0±1.8 years of follow-up, SVA occurred in 39 patients (34%). NSVT (HR, 4.47 [95% CI, 1.87-10.72]; P=0.001) and VT inducibility (HR, 3.08 [95% CI, 1.08-8.81]; P=0.036) were independently associated with SVA during follow-up. A bivariable model including only noninvasively acquired parameters also allowed identification of a high-risk subgroup (ie, those with both NSVT and LGE on CMR). The findings remained similar when only patients without prior SVA were included. CONCLUSIONS: In patients with DCM, NSVT on Holter and VT inducibility during electrophysiology study predict SVA during follow-up independent of LGE on CMR. NSVTs may serve as an initiator, and sustained VT inducibility indicates the presence of the substrate for SVA in DCM. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01940081.

National networking in rare diseases and reduction of cardiac burden in thalassemia major.

AIMS: A tailored chelation therapy guided by magnetic resonance imaging (MRI) is a strategy to improve the prognosis in iron-loaded patients, in many cases still hampered by limited MRI availability. In order to address this issue, the Myocardial Iron Overload in Thalassemia (MIOT) network was established in Italy and we aimed to describe the impact of 10-year activity of this network on cardiac burden in thalassemia major (TM). METHODS AND RESULTS: Within the MIOT network, 1746 TM patients (911 females; mean age 31.2 ± 9.1 years) were consecutively enrolled and prospectively followed by 70 thalassemia and 10 MRI centres. Patients were scanned using a multiparametric approach for assessing myocardial iron overload (MIO), biventricular function, and myocardial fibrosis. At the last MRI scan, a significant increase in global heart T2* values and a significantly higher frequency of patients with no MIO (all segmental T2* ≥20 ms) were detected, with a concordant improvement in biventricular function, particularly in patients with baseline global heart T2* <20 ms. Forty-seven percentage of patients changed the chelation regimen based on MRI. The frequency of heart failure (HF) significantly decreased after baseline MRI from 3.5 to 0.8% (P < 0.0001). Forty-six patients died during the study, and HF accounted for 34.8% of deaths. CONCLUSION: Over 10 years, continuous monitoring of cardiac iron and a tailored chelation therapy allowed MIO reduction, with consequent improvement of cardiac function and reduction of cardiac complications and mortality from MIO-related HF. A national networking for rare diseases therefore proved effective in improving the care and reducing cardiac outcomes of TM patients.

Substrate Characterization and Outcome of Catheter Ablation of Ventricular Tachycardia in Patients With Nonischemic Cardiomyopathy and Isolated Epicardial Scar.

BACKGROUND: The substrate for ventricular tachycardia (VT) in left ventricular (LV) nonischemic cardiomyopathy may be epicardial. We assessed the prevalence, location, endocardial electrograms, and VT ablation outcomes in LV nonischemic cardiomyopathy with isolated epicardial substrate. METHODS: Forty-seven of 531 (9%) patients with LV nonischemic cardiomyopathy and VT demonstrated normal endocardial (>1.5 mV)/abnormal epicardial bipolar low-voltage area (LVA, <1.0 mV and signal abnormality). Abnormal endocardial unipolar LVA (≤8.3 mV) and endocardial bipolar split electrograms and predictors of ablation success were assessed. RESULTS: Epicardial bipolar LVA (27.3 cm2 [interquartile range, 15.8-50.0]) localized to basal (40), mid (8), and apical (3) LV with basal inferolateral LV most common (28/47, 60%). Of 44 endocardial maps available, 40 (91%) had endocardial unipolar LVA (24.5 cm2 [interquartile range, 9.4-68.5]) and 29 (67%) had characteristic normal amplitude endocardial split electrograms opposite the epicardial LVA. At mean of 34 months, the VT-free survival was 55% after one and 72% after multiple procedures. Greater endocardial unipolar LVA than epicardial bipolar LVA (hazard ratio, 10.66 [CI, 2.63-43.12], P=0.001) and number of inducible VTs (hazard ratio, 1.96 [CI, 1.27-3.00], P=0.002) were associated with VT recurrence. CONCLUSIONS: In patients with LV nonischemic cardiomyopathy and VT, the substrate may be confined to epicardial and commonly basal inferolateral. LV endocardial unipolar LVA and normal amplitude bipolar split electrograms identify epicardial LVA. Ablation targeting epicardial VT and substrate achieves good long-term VT-free survival. Greater endocardial unipolar than epicardial bipolar LVA and more inducible VTs predict VT recurrence.

Constrictive pericarditis in the setting of repeated chest trauma in a mixed martial arts fighter.

BACKGROUND: Constrictive pericarditis (CP) is characterized by scarring and loss of elasticity of the pericardium. This case demonstrates that mixed martial arts (MMA) is a previously unrecognized risk factor for CP, diagnosis of which is supported by cardiac imaging, right and left heart catheterization, and histological findings of dense fibrous tissue without chronic inflammation. CASE PRESENTATION: A 47-year-old Caucasian male former mixed martial arts (MMA) fighter from the Western United States presented to liver clinic for elevated liver injury tests (LIT) and a 35-pound weight loss with associated diarrhea, lower extremity edema, dyspnea on exertion, and worsening fatigue over a period of 6 months. Past medical history includes concussion, right bundle branch block, migraine headache, hypertension, chronic pain related to musculoskeletal injuries and fractures secondary to MMA competition. Involvement in MMA was extensive with an 8-year history of professional MMA competition and 13-year history of MMA fighting with recurrent trauma to the chest wall. The patient also reported a 20-year history of performance enhancing drugs including testosterone. Physical exam was notable for elevated jugular venous pressure, hepatomegaly, and trace peripheral edema. An extensive workup was performed including laboratory studies, abdominal computerized tomography, liver biopsy, echocardiogram, and cardiac magnetic resonance imaging. Finally, right and left heart catheterization-the gold standard-confirmed discordance of the right ventricle-left ventricle, consistent with constrictive physiology. Pericardiectomy was performed with histologic evidence of chronic pericarditis. The patient's hospital course was uncomplicated and he returned to NYHA functional class I. CONCLUSIONS: CP can be a sequela of recurrent pericarditis or hemorrhagic effusions and may have a delayed presentation. In cases of recurrent trauma, CP may be managed with pericardiectomy with apparent good outcome. Further studies are warranted to analyze the occurrence of CP in MMA so as to better define the risk in such adults.

Right ventricular endomyocardial biopsy in patients with cardiac magnetic resonance showing left ventricular myocarditis.

AIMS: The aim of this study was to evaluate the sensitivity of right ventricular endomyocardial biopsy (EMB) in myocarditis patients with cardiac magnetic resonance (CMR) and electroanatomical mapping (EAM) showing left ventricular abnormalities. METHODS: We performed right ventricular EMB in 144 consecutive patients (66% men, age 43 ±â€Š15 years) with acute symptoms and CMR-proved diagnosis of left ventricular myocarditis. Right ventricular EMB sensitivity has been evaluated in patients with different localization and extension of abnormal substrate at both CMR and -- when performed -- EAM. Abnormal substrate was defined, respectively, by late gadolinium enhancement (LGE) and low-voltage areas (LVAs). RESULTS: Globally, right ventricular EMB sensitivity was 87.5%. EMB-negative cases had significantly smaller fragment sizes (cumulative area 2.8 ±â€Š1.7 vs. 3.8 ±â€Š1.8 mm2, P = 0.023), and lower LGE surface extension (24.7 ±â€Š14.2 vs. 38.5 ±â€Š20.2%, P = 0.006) and transmurality (32.0 ±â€Š26.1 vs. 49.3 ±â€Š22.6, P = 0.003). Right ventricular EMB sensitivity in patients with LGE involving both right ventricular and interventricular septum (IVS), isolated right ventricular or IVS, and remote left ventricular areas (n = 10, 49 and 67 cases) was 83.3, 84.4 and 90.5%, respectively (P = 0.522). Overall, 34 patients (23.6%) underwent EAM. On the basis of EAM, right ventricular EMB sensitivity was 85.3%: in detail, it was 50.0, 88.2 and 86.7% in patients with both right ventricular and IVS, isolated right ventricular/IVS and distant left ventricular involvement (n = 2, 17 and 15, respectively, P > 0.05). Sample size area was the only factor associated with right ventricular EMB sensitivity (hazard ratio = 1.6/mm2, 95% confidence interval 1.1-2.4, P = 0.013). CONCLUSION: Right ventricular EMB is still an accurate technique to confirm diagnosis in patients with CMR-proved left ventricular myocarditis. In particular, provided there is an adequate sample size, its sensitivity is comparable among patients with heterogeneous LGE or LVA localization.

Quantification of Myocardial Deformation Applying CMR-Feature-Tracking-All About the Left Ventricle?

PURPOSE OF REVIEW: Cardiac magnetic resonance-feature-tracking (CMR-FT)-based deformation analyses are key tools of cardiovascular imaging and applications in heart failure (HF) diagnostics are expanding. In this review, we outline the current range of application with diagnostic and prognostic implications and provide perspectives on future trends of this technique. RECENT FINDINGS: By applying CMR-FT in different cardiovascular diseases, increasing evidence proves CMR-FT-derived parameters as powerful diagnostic and prognostic imaging biomarkers within the HF continuum partly outperforming traditional clinical values like left ventricular ejection fraction. Importantly, HF diagnostics and deformation analyses by CMR-FT are feasible far beyond sole left ventricular performance evaluation underlining the holistic nature and accuracy of this imaging approach. As an established and continuously evolving technique with strong prognostic implications, CMR-FT deformation analyses enable comprehensive cardiac performance quantification of all cardiac chambers.

Rotigaptide Infusion for the First 7 Days After Myocardial Infarction-Reperfusion Reduced Late Complexity of Myocardial Architecture of the Healing Border-Zone and Arrhythmia Inducibility.

Background Survivors of myocardial infarction are at increased risk of late ventricular arrhythmias, with infarct size and scar heterogeneity being key determinants of arrhythmic risk. Gap junctions facilitate the passage of small ions and morphogenic cell signaling between myocytes. We hypothesized that gap junctions enhancement during infarction-reperfusion modulates structural and electrophysiological remodeling and reduces late arrhythmogenesis. Methods and Results Infarction-reperfusion surgery was carried out in male Sprague-Dawley rats followed by 7 days of rotigaptide or saline administration. The in vivo and ex vivo arrhythmogenicity was characterized by programmed electrical stimulation 3 weeks later, followed by diffusion-weighted magnetic resonance imaging and Masson's trichrome histology. Three weeks after 7-day postinfarction administration of rotigaptide, ventricular tachycardia/ventricular fibrillation was induced on programmed electrical stimulation in 20% and 53% of rats, respectively (rotigaptide versus control), resulting in reduction of arrhythmia score (3.2 versus 1.4, P=0.018), associated with the reduced magnetic resonance imaging parameters fractional anisotropy (fractional anisotropy: -5% versus -15%; P=0.062) and mean diffusivity (mean diffusivity: 2% versus 6%, P=0.042), and remodeling of the 3-dimensional laminar structure of the infarct border zone with reduction of the mean (16° versus 19°, P=0.013) and the dispersion (9° versus 12°, P=0.015) of the myofiber transverse angle. There was no change in ECG features, spontaneous arrhythmias, or mortality. Conclusions Enhancement of gap junctions function by rotigaptide administered during the early healing phase in reperfused infarction reduces later complexity of infarct scar morphology and programmed electrical stimulation-induced arrhythmias, and merits further exploration as a feasible and practicable intervention in the acute myocardial infarction management to reduce late arrhythmic risk.

Myocardial Iron Deficiency Quantification and Effective Cardiac Iron Management Strategy Exploration evaluated by Cardiac T2* Mapping in End-Stage Renal Disease Patients.

PURPOSE: To explore myocardial iron content using Cardiac T2* Mapping in dialysis patients undergoing oral iron therapy or intravenous iron supplements compared to healthy controls. METHODS: Fifty-nine dialysis patients, including 30 peritoneal dialysis (PD) patients who underwent oral iron therapy, 29 hemodialysis (HD) dialysis patients who underwent intravenous iron supplements, and 30 healthy controls were included in the study. Cardiac MRI, including cine, T2 stir, and T2* mapping, was conducted at 3.0T. Quantitive T2* mapping, Cine imaging analysis was performed by two radiologists using cvi42. RESULTS: The global cardiac T2* value was higher in dialysis patients than in healthy controls (27.1 ± 6.29 ms versus 24.6 ± 3.60 ms, p< 0.05). The global cardiac T2* value of PD patients was higher than that of HD patients (28.5 ± 4.30 ms versus 25.x7 ± 3.54 ms, p< 0.05). The anteroseptal cardiac T2* value was higher in PD patients than in healthy controls (32.0 ± 4.49 ms versus 27.8 ± 4.02 ms, p< 0.05). The global T2* value negatively correlated with left ventricular ejection fraction (LVEF), peak radial strain, circumferential strain, and longitudinal strain. CONCLUSION: Our study confirmed that PD patients have myocardial iron deficiency despite undergoing oral iron therapy compared to HD patients who received intravenous iron treatments. And the Cardiac T2* value was found to be an independent risk factor and predictor of LVEF and left ventricular altered mechanics. Intravenous iron supplements may be an effective cardiac iron management strategy in patients with HD-dependent end-stage renal disease.

Cardiac T2* MR in patients with thalassemia major: a 10-year long-term follow-up.

The consequence of regular blood transfusion in patients with thalassemia major (TM) is iron overload. Herein, we report the long-term impact of chelation on liver iron concentration (LIC) and cardiac T2* MR in patients with TM. This is a retrospective cohort study over 10 years of adolescents and adults with TM aged at least 10 years who had their first cardiac T2* MR between September 2006 and February 2007. One-year chelation therapy was considered the unit of analysis. A total of 99 patients were included in this study with a median age of 18 years. The median cardiac T2* MR and LIC at baseline were 19 ms and 11.6 mg/g dw, respectively. During follow-up, 18 patients died and six underwent successful bone marrow transplantation. Factors associated with decreased survival were older age (HR 1.12, p = 0.014) and high risk cardiac T2* (HR 8.04, p = 0.004). The median cardiac T2* and LIC significantly improved over the 10-year follow-up period (p = 0.000011 and 0.00072, respectively). In conclusion, this long-term "real-life" study confirms that low cardiac T2* adversely impacts the overall survival in patients with TM. Higher baseline LIC predicts a larger reduction in LIC, and lower baseline cardiac T2* predicts a larger improvement in T2*.

Comparison of global strain values of myocardium in beta-thalassemia major patients with iron load using specific feature tracking in cardiac magnetic resonance imaging.

Thalassemia defined a spectrum of diseases characterized by reduced or absent production of one of the globin chains of hemoglobin. High iron deposition in the myocardium may cause functional impairment even before any changes in left ventricular (LV) ejection fraction. These impairments may appear as changes in strain values. Early detection of myocardial dysfunction is essential for improving survival and preventing further complications. Therefore, this study aims to evaluate the cardiac strain patterns by Feature Tracking -Cardiac Magnetic Resonance Imaging (FT-CMR) method and their correlation with T2* values as a new parameter in determining myocardial iron overload (MIO). In this retrospective investigation, ninety-one patients with B-thalassemia major included from May 2016 to July 2019. Twenty-three healthy subjects, also incorporated as a control group. CMR used to evaluate ventricular volumes, LVEF, and the amount of myocardial T2*. Moreover, Global Longitudinal Strain (GLS), Global Circumferential Strain (GCS), and Global Radial Strain (GRS) were measured and analyzed in both rights and left ventricles. Correlations of cardiac T2* with GLS, GCS, and GRS were evaluated. The optimal cutoff value of GLS for prediction of cardiac T2* < 20 ms (as an indicator of inadequate chelation) calculated as well. There were significant correlations between cardiac T2* with LV GLS, LV GCS, and right ventricular GLS (p < 0.05 for each one). Moreover, a significant difference detected between the group of TM - MIO and TM + MIO and control group in terms of GLS (p < 0.001). The optimal cutoff value of GLS for prediction of cardiac T2* < 20 ms was at - 16.5% with sensitivity and specificity of 73% and 63%, respectively. Our study demonstrates that strain values measured by FT and myocardial T2* values are correlated. FT-CMR can be considered as an efficient tool for early detection of iron deposition and its effects on cardiac tissue so that proper and timely modification could have applied to chelation therapy.

Imaging, biomarker and invasive assessment of diffuse left ventricular myocardial fibrosis in atrial fibrillation.

BACKGROUND: Using cardiovascular magnetic resonance imaging (CMR), it is possible to detect diffuse fibrosis of the left ventricle (LV) in patients with atrial fibrillation (AF), which may be independently associated with recurrence of AF after ablation. By conducting CMR, clinical, electrophysiology and biomarker assessment we planned to investigate LV myocardial fibrosis in patients undergoing AF ablation. METHODS: LV fibrosis was assessed by T1 mapping in 31 patients undergoing percutaneous ablation for AF. Galectin-3, coronary sinus type I collagen C terminal telopeptide (ICTP), and type III procollagen N terminal peptide were measured with ELISA. Comparison was made between groups above and below the median for LV extracellular volume fraction (ECV), followed by regression analysis. RESULTS: On linear regression analysis LV ECV had significant associations with invasive left atrial pressure (Beta 0.49, P = 0.008) and coronary sinus ICTP (Beta 0.75, P < 0.001), which remained significant on multivariable regression. CONCLUSION: LV fibrosis in patients with AF is associated with left atrial pressure and invasively measured levels of ICTP turnover biomarker.

Ventricular arrhythmia ablation lesions detectability and temporal changes on cardiac magnetic resonance.

BACKGROUND: Cardiac magnetic resonance (CMR) characteristics of ventricular radiofrequency ablation (RFA) lesions have only been incompletely defined. AIM: To determine the detectability and imaging characteristics of ventricular RFA lesions in an unselected patient cohort undergoing ventricular arrhythmia ablation. METHODS AND RESULTS: A retrospective chart review (n = 249) identified 36 patients with either pre-/postablation CMR (n = 14) or only postablation CMR (n = 22). Ablation lesions could be identified in 50% (n = 18) of patients. Nonvisualized lesions had more preexisting transmural late gadolinium enhancement (LGE) >75% at the ablation sites (21% vs 0.0%, P = .042), more prevalent ICD artifact (50% vs 0%, P = .001), and lower ejection fraction (35.8 ± 14.2% vs 45.3 ± 13.4%, P = .048). Early CMR imaging demonstrated a central "black" signal void (microvascular obstruction [MVO], n = 12, 67%) up to 32 days post-RFA, whereas late imaging showed a homogenously "white" gadolinium enhancement pattern (n = 6, 33%). MVO was only observed in nonfibrotic myocardium without preexisting LGE (n = 12) but was not observed in the scar with preexisting LGE (n = 3, P = .002) suggesting different wash-in/wash-out kinetics in scar/nonscar myocardium. Signal intensity (1909 vs 2534, P = .009) and contrast-to-noise ratio (-7.8 vs 16.3, P = .009) were significantly different between MVO and LGE lesions, respectively. CONCLUSION: Ventricular ablation lesions visualization is negatively affected by preexisting transmural scar, ICD artifact, and low ejection fraction. The transition of "black" MVO appearance to "white" LGE appearance on CMR occurs around 1 month following ablation, suggesting a change in histological characteristics of ablation lesions. This may affect the utility of CMR in the evaluation of the ventricular lesions, when undergoing real-time or repeat VT ablations.

Acetabular avascular necrosis following high-dose steroid treatment and chemotherapy for leukemia : Computer tomography analysis of treatment with impaction bone grafting.

Avascular necrosis (AVN) of the bone is thought to be a serious complication of treatment for acute lymphoblastic leukemia (ALL). The acetabulum is an unusual area to be affected by AVN, and there are currently no reports of successful joint salvage procedures found in the literature. We present a case of a 20-year-old man with ALL who was diagnosed with debilitating AVN of both acetabula 2 years following initial diagnosis of ALL and treatment with a multi-agent chemotherapy regimen including high-dose corticosteroids. After unsuccessful treatment with bisphosphonate therapy, the acetabular AVN underwent bilateral curettage and impaction bone grafting to prevent collapse of subchondral fractures with the hope of salvaging both hip joints. Computer tomography (CT) of the AVN affected areas, pre- and post-bone impaction grafting, demonstrated healing of the subchondral fractures and a doubling of bone density that was maintained at 2 years after surgery. The patient resumed full weight-bearing at 3 months after first surgery, continues to ambulate unrestricted, and remains pain free 3 years post-surgery.

Extracellular Volume Associates With Outcomes More Strongly Than Native or Post-Contrast Myocardial T1.

OBJECTIVES: Because risk stratification data represents a key domain of biomarker validation, we compared associations between outcomes and various cardiovascular magnetic resonance (CMR) metrics quantifying myocardial fibrosis (MF) in noninfarcted myocardium: extracellular volume fraction (ECV), native T1, post-contrast T1, and partition coefficient. BACKGROUND: MF associates with vulnerability to adverse events (e.g., mortality and hospitalization for heart failure [HHF]), but investigators still debate its optimal measurement; most histological validation data show strongest ECV correlations with MF. METHODS: We enrolled 1,714 consecutive patients without amyloidosis or hypertrophic cardiomyopathy from a single CMR referral center serving an integrated healthcare network. We measured T1 (MOdified Look-Locker Inversion recovery [MOLLI]) in nonenhanced myocardium, averaged from 2 short-axis slices (basal and mid) before and 15 to 20 min after a gadolinium contrast bolus. We compared chi-square test values from CMR MF measures in univariable and multivariable Cox regression models. We assessed "dose-response" relationships in Kaplan-Meier curves using log-rank statistics for quartile strata. We also computed net reclassification improvement (NRI) and integrated discrimination improvement (IDI for Cox models with ECV vs. native T1). RESULTS: Over a median of 5.6 years, 374 events occurred after CMR (162 HHF events and 279 deaths, 67 with both). ECV yielded the best separation of Kaplan-Meier curves and the highest log-rank statistics. In univariable and multivariable models, ECV associated most strongly with outcomes, demonstrating the highest chi-square test values. Native T1 or post-contrast T1 did not associate with outcomes in the multivariable model. ECV provided added prognostic value to models with native T1, for example, in multivariable models IDI = 0.0037 (95% confidence interval [CI]: 0.0009 to 0.0071), p = 0.02; NRI = 0.151 (95% CI: 0.022 to 0.292), p = 0.04. CONCLUSIONS: Analogous to histological previously published validation data, ECV myocardial fibrosis measures exhibited more robust associations with outcomes than other surrogate CMR MF measures. Superior risk stratification by ECV supports claims that ECV optimally measures MF in noninfarcted myocardium.

Evaluation of Risk Prediction Models of Atrial Fibrillation (from the Multi-Ethnic Study of Atherosclerosis [MESA]).

Atrial fibrillation (AF) is prevalent and strongly associated with higher cardiovascular disease (CVD) risk. Machine learning is increasingly used to identify novel predictors of CVD risk, but prediction improvements beyond established risk scores are uncertain. We evaluated improvements in predicting 5-year AF risk when adding novel candidate variables identified by machine learning to the CHARGE-AF Enriched score, which includes age, race/ethnicity, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and NT-proBNP. We included 3,534 participants (mean age, 61.3 years; 52.0% female) with complete data from the prospective Multi-Ethnic Study of Atherosclerosis. Incident AF was defined based on study electrocardiograms and hospital discharge diagnosis ICD-9 codes, supplemented by Medicare claims. Prediction performance was evaluated using Cox regression and a parsimonious model was selected using LASSO. Within 5 years of baseline, 124 participants had incident AF. Compared with the CHARGE-AF Enriched model (c-statistic, 0.804), variables identified by machine learning, including biomarkers, cardiac magnetic resonance imaging variables, electrocardiogram variables, and subclinical CVD variables, did not significantly improve prediction. A 23-item score derived by machine learning achieved a c-statistic of 0.806, whereas a parsimonious model including the clinical risk factors age, weight, current smoking, NT-proBNP, coronary artery calcium score, and cardiac troponin-T achieved a c-statistic of 0.802. This analysis confirms that the CHARGE-AF Enriched model and a parsimonious 6-item model performed similarly to a more extensive model derived by machine learning. In conclusion, these simple models remain the gold standard for risk prediction of AF, although addition of the coronary artery calcium score should be considered.

New Adjusted Cutoffs for "Normal" Endocardial Voltages in Patients With Post-Infarct LV Remodeling.

OBJECTIVES: This study sought to determine new reference cutoffs for normal unipolar voltage (UV) and bipolar voltage (BV) that would be adjusted for the LV remodeling. BACKGROUND: The definition of "normal" left ventricular (LV) endocardial voltage in patients with post-infarct scar is still lacking. The reference voltage of the noninfarcted myocardium (NIM) may differ between patients depending on LV structural remodeling and the ensuing interstitial fibrosis. METHODS: Electroanatomic voltage mapping was integrated with isotropic late gadolinium-enhanced cardiac magnetic resonance in 15 patients with nonremodeled LV and 12 patients with remodeled LV (end-systolic volume index >50 ml/m2 with ejection fraction <47% assessed by cardiac magnetic resonance). Reference voltages (fifth percentile values) were determined from pooled NIM segments without late gadolinium enhancement. RESULTS: The cutoffs for normal BV and UV were ≥3.0 and ≥6.7 mV for nonremodeled LV and ≥2.1 and ≥6.4 mV for remodeled LV. Endocardial low-voltage area (LVA) defined by the adjusted cutoffs corresponded better to late gadolinium enhancement-detected scar than did LVA defined by uniform cutoffs. In 15 patients who underwent successful ablation of ventricular tachycardia, the LVA contained >97% of targeted evoked delayed potentials. Insights from whole-heart T1 mapping revealed more fibrotic NIM in patients with remodeled LV compared with nonremodeled LV. CONCLUSIONS: This study found substantial differences in endocardial voltage of NIM in post-infarct patients with remodeled versus nonremodeled LV. The new adjusted cutoffs for "normal" BV and UV enable a patient-tailored approach to electroanatomic voltage mapping of LV.

Extent and spatial distribution of left atrial arrhythmogenic sites, late gadolinium enhancement at magnetic resonance imaging, and low-voltage areas in patients with persistent atrial fibrillation: comparison of imaging vs. electrical parameters of fibrosis and arrhythmogenesis.

AIMS: Atrial fibrosis contributes to arrhythmogenesis in atrial fibrillation and can be detected by MRI or electrophysiological mapping. The current study compares the spatial correlation between delayed enhancement (DE) areas to low-voltage areas (LVAs) and to arrhythmogenic areas with spatio-temporal dispersion (ST-Disp) or continuous activity (CA) in atrial fibrillation (AF). METHODS AND RESULTS: Sixteen patients with persistent AF (nine long-standing) underwent DE-magnetic resonance imaging (1.25 mm × 1.25 mm × 2.5 mm) prior to pulmonary vein isolation. Left atrial (LA) voltage mapping was acquired in AF and the regional activation patterns of 7680 AF wavelets were analysed. Sites with ST-Disp or CA were characterized (voltage, duration) and their spatial relationship to DE areas and LVAs <0.5 mV was assessed. Delayed enhancement areas and LVAs covered 55% and 24% (P < 0.01) of total LA surface, respectively. Delayed enhancement area was present at 61% of LVAs, whereas low voltage was present at 28% of DE areas. Most DE areas (72%) overlapped with atrial high-voltage areas (>0.5 mV). Spatio-temporal dispersion and CA more frequently co-localized with LVAs than with DE areas (78% vs. 63%, P = 0.02). Regional bipolar voltage of ST-Disp vs. CA was 0.64 ± 0.47 mV vs. 0.58 ± 0.51 mV. All 28 ST-Disp and 56 CA areas contained electrograms with prolonged duration (115 ± 14 ms) displaying low voltage (0.34 ± 0.11 mV). CONCLUSION: A small portion of DE areas and LVAs harbour the arrhythmogenic areas displaying ST-Disp or CA. Most arrhythmogenic activities co-localized with LVAs, while there was less co-localization with DE areas. There is an important mismatch between DE areas and LVAs which needs to be considered when used as target for catheter ablation.

3D Myocardial Scar Prediction Model Derived from Multimodality Analysis of Electromechanical Mapping and Magnetic Resonance Imaging.

Many cardiac catheter interventions require accurate discrimination between healthy and infarcted myocardia. The gold standard for infarct imaging is late gadolinium-enhanced MRI (LGE-MRI), but during cardiac procedures electroanatomical or electromechanical mapping (EAM or EMM, respectively) is usually employed. We aimed to improve the ability of EMM to identify myocardial infarction by combining multiple EMM parameters in a statistical model. From a porcine infarction model, 3D electromechanical maps were 3D registered to LGE-MRI. A multivariable mixed-effects logistic regression model was fitted to predict the presence of infarct based on EMM parameters. Furthermore, we correlated feature-tracking strain parameters to EMM measures of local mechanical deformation. We registered 787 EMM points from 13 animals to the corresponding MRI locations. The mean registration error was 2.5 ± 1.16 mm. Our model showed a strong ability to predict the presence of infarction (C-statistic = 0.85). Strain parameters were only weakly correlated to EMM measures. The model is accurate in discriminating infarcted from healthy myocardium. Unipolar and bipolar voltages were the strongest predictors.

Misdiagnosis of ARVC leading to inappropriate ICD implant and subsequent ICD removal - lessons learned.

INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited progressive cardiomyopathy characterized by frequent life-threatening arrhythmias. The diagnosis of ARVC is challenging and is on the basis of a set of major and minor criteria as described by the modified Task Force Criteria (TFC). We report our clinical experience in a series of patients who were misdiagnosed with ARVC and subsequently underwent removal of their implantable cardioverter defibrillator (ICD) after a re-evaluation at our center. METHODS AND RESULTS: We studied 12 patients who were misdiagnosed with ARVC and had ICD implantation before our assessment. All patients had a repeat evaluation and were scored according to TFC before ICD removal. Cardiac magnetic resonance imaging (CMR) studies performed at outside institutions during the initial evaluation were reported abnormal and classified as meeting major TFC in ninety percent of patients. The most common abnormality reported was fatty infiltration of the right ventricular (RV) free wall and/or presence of focal intra-myocardial fat in six patients (50%). On re-evaluation, none of these findings fulfilled the TFC for the diagnosis. CONCLUSION: This study demonstrated that high dependence on misinterpretation of CMR along with a misunderstanding of the TFC evaluation are the main reasons for the misdiagnosis of ARVC. Despite the updated criteria for almost a decade, this study reminds that the diagnosis of ARVC is complex and hence careful TFC evaluation and consideration of multiple cardiac test results should be the focused approach for clinicians when confronted with suspected ARVC patients.