Association between genetic variants in the HIF1A-VEGF pathway and left ventricular regional myocardial deformation in patients with hypertrophic cardiomyopathy.

BACKGROUND: Information on genetic etiology of pediatric hypertrophic cardiomyopathy (HCM) rarely aids in risk stratification and prediction of disease onset. Little data exist on the association between genetic modifiers and phenotypic expression of myocardial performance, hampering an individual precision medicine approach. METHODS: Single-nucleotide polymorphism genotyping for six previously established disease risk alleles in the hypoxia-inducible factor-1α-vascular endothelial growth factor pathway was performed in a pediatric cohort with HCM. Findings were correlated with echocardiographic parameters of systolic and diastolic myocardial deformation measured by two-dimensional (2-D) speckle-tracking strain. RESULTS: Twenty-five children (6.1 ± 4.5 years; 69% male) with phenotypic and genotypic (60%) HCM were included. Out of six risk alleles tested, one, VEGF1 963GG, showed an association with reduced regional systolic and diastolic left ventricular (LV) myocardial deformation. Moreover, LV average and segmental systolic and diastolic strain and strain rate were significantly reduced, as assessed by the standardized difference, in patients harboring the risk allele. CONCLUSIONS: This is the first study to identify an association between a risk allele in the VEGF pathway and regional LV myocardial function, with the VEGF1 963GG allele associated with reduced LV systolic and diastolic myocardial performance. While studies are needed to link this information to adverse clinical outcomes, this knowledge may help in risk stratification and patient management in HCM. IMPACT: Risk allele in the VEGF gene impacts on LV myocardial deformation phenotype in children with HCM. LV 2-D strain is significantly reduced in patients with risk allele compared to non-risk allele patients within HCM patient groups. Describes that deficiencies in LV myocardial performance in children with HCM are associated with a previously identified risk allele in the angiogenic transcription factor VEGF. First study to identify an association between a risk allele in the VEGF pathway and regional LV myocardial deformation measured by 2-D strain in children with HCM.

Exercise Capacity and Self-Efficacy are Associated with Moderate-to-Vigorous Intensity Physical Activity in Children with Congenital Heart Disease.

This study sought to determine whether exercise capacity, self-efficacy, and gross motor skills are associated with moderate-to-vigorous physical activity (MVPA) levels in children, and if these associations differ by congenital heart disease (CHD) type. Medical history was abstracted from chart review. We assessed MVPA levels (via accelerometry), percent-predicted peak oxygen consumption ([Formula: see text] cardiopulmonary exercise test), gross motor skill percentiles (test of gross motor development version-2), and self-efficacy [children's self-perceptions of adequacy and predilection for physical activity scale (CSAPPA scale)]. CHD patients (n = 137, range 4-12 years) included children with a repaired atrial septal defect (n = 31, mean ± standard deviation MVPA = 454 ± 246 min/week), transposition of the great arteries after the arterial switch operation (n = 34, MVPA = 423 ± 196 min/week), tetralogy of Fallot after primary repair (n = 37, MVPA = 389 ± 211 min/week), or single ventricle after the Fontan procedure (n = 35, MVPA = 405 ± 256 min/week). MVPA did not differ significantly between CHD groups (p = 0.68). Higher MVPA was associated with a higher percent-predicted [Formula: see text] (EST[95% CI] = 16.9[-0.2, 34] MVPA min/week per 10% increase in percent-predicted [Formula: see text] p = 0.05) and higher self-efficacy (EST[95% CI] = 5.2[1.0, 9.3] MVPA min/week per 1-unit increase in CSAPPA score, p = 0.02), after adjustment for age, sex, and testing seasonality, with no association with CHD type. Higher MVPA was not associated with gross motor skill percentile (p = 0.92). There were no significant interactions between CHD type and percent-predicted [Formula: see text] self-efficacy scores, and gross motor skill percentiles regarding their association with MVPA (p > 0.05 for all). Greater MVPA was associated with higher exercise capacity and self-efficacy, but not gross motor skills.

Clinical Impact of Stent Implantation for Coarctation of the Aorta with Associated Hypoplasia of the Transverse Aortic Arch.

The aim of this study was to explore the clinical impact of transverse aortic arch hypoplasia (TAH) after stent implementation for isthmal coarctation of the aorta (CoA). From a retrospective chart review, 51 children (median age 11.1 years) were identified who had TAH and a CoA stent implanted between 10/1995 and 4/2015. Arm-leg cuff blood pressure measurements, echocardiographic arch imaging, and 24-h ambulatory blood pressure monitoring, prior to and after stent implantation, were reviewed. At catheterization, peak systolic gradients across the CoA's were 25 mmHg before and 4 mmHg after stent implantation. At a median 37-month follow-up, echocardiographic imaging showed no significant catch-up growth in the transverse arch (median z-score; proximal and distal arch -1.54 and -1.99 vs. -1.78 and -1.63, p = 0.13 and 0.90). A trend to increasing systolic blood pressure (SBP) differentials between the right and left arms was noted (11 mmHg [prior to]; 16 mmHg [follow-up], p = 0.09). Age-adjusted percentiles for right arm SBP decreased from 99.7% prior to, and 87.6% in follow-up (p < 0.001). The median time to re-intervention was 5.6 years (95% CI [2.8, 7.8]) and the proportion of children using anti-hypertensive in follow-up was not significantly different before the implantation (38% [prior to]; 45% [follow-up]). Elevated right arm blood pressure persists after successful stent implantation in the setting of associated TAH and there appears to be no catch-up growth of the transverse arch with time. Medical management can be difficult and approaches to surgical arch augmentation or stent implantation should be considered to avoid unilateral arm hypertension.

Reported electronic cigarette use among adolescents in the Niagara region of Ontario.

BACKGROUND: Use of electronic cigarettes (e-cigarettes) among adolescents has not been fully described, in particular their motivations for using them and factors associated with use. We sought to evaluate the frequency, motivations and associated factors for e-cigarette use among adolescents in Ontario. METHODS: We conducted a cross-sectional study in the Niagara region of Ontario, Canada, involving universal screening of students enrolled in grade 9 in co-operation with the Heart Niagara Inc. Healthy Heart Schools' Program (for the 2013-2014 school year). We used a questionnaire to assess cigarette, e-cigarette and other tobacco use, and self-rated health and stress. We assessed household income using 2011 Canadian census data by matching postal codes to census code. RESULTS: Of 3312 respondents, 2367 answered at least 1 question in the smoking section of the questionnaire (1274 of the 2367 respondents [53.8%] were male, with a mean [SD] age of 14.6 [0.5] yr) and 2292 answered the question about use of e-cigarettes. Most respondents to the questions about use of e-cigarettes (n = 1599, 69.8%) had heard of e-cigarettes, and 380 (23.8%) of these respondents had learned about them from a store sign or display. Use of e-cigarettes was reported by 238 (10.4%) students. Most of the respondents who reported using e-cigarettes (171, 71.9%) tried them because it was "cool/fun/new," whereas 14 (5.8%) reported using them for smoking reduction or cessation. Male sex, recent cigarette or other tobacco use, family members who smoke and friends who smoke were strongly associated with reported e-cigarette use. Reported use of e-cigarettes was associated with self-identified fair/poor health rating (odds ratio [OR] 1.9 (95% confidence interval [CI] 1.2-3.0), p < 0.001), high stress level (OR 1.7 (95% CI 1.1-2.7), p < 0.001) and lower mean (33.4 [8.4] × $1000 v. 36.1 [10.7] × $1000, p = 0.001) and median [interquartile range] (26.2 [5.6] × $1000 v. 28.1 [5.7] × $1000) household incomes. INTERPRETATION: Use of e-cigarettes is common among adolescents in the Niagara region and is associated with sociodemographic features. Engaging in seemingly exciting new behaviours appears to be a key motivating factor rather than smoking cessation.

Association between gastrointestinal events and osteoporosis treatment initiation in women diagnosed with osteoporosis in France: a retrospective analysis.

BACKGROUND: A substantial portion of women diagnosed with osteoporosis (OP) do not initiate pharmacotherapy to reduce fracture risk. In clinical practice, gastrointestinal (GI) events have been linked with OP therapy discontinuation. However, there is limited research examining GI events as barrier to treatment initiation following an OP diagnosis. The objective of this study was to examine the association between gastrointestinal (GI) events and osteoporosis (OP) treatment initiation among post-menopausal women diagnosed with osteoporosis in France. METHODS: A retrospective claims analysis of the Mediplus France database during 1997 to 2010 identified women aged ≥ 55 with an OP diagnosis and without prior OP treatment (first diagnosis date was defined as the index date). GI events were identified during the 1 year pre-index and up to 1 year post-index. OP treatment initiation post-index was identified based on the presence of claims for any bisphosphonate (BIS) or non-BIS OP medication within 1 year post-index. Multivariate models (logistic regression, Cox proportional hazards regression and discrete choice) adjusted for pre-index patient characteristics were used to assess the association of pre- and post-index GI events with the likelihood of initiating OP treatment, and the type of treatment initiated (BIS vs. non-BIS). RESULTS: A total of 10,292 women (mean age 70.3 years) were identified; only 25% initiated OP treatment. Post-index GI events occurred in 11.5% of patients, and were associated with a 75.7% lower likelihood of initiating OP treatment. Among treated patients, a discrete choice model estimated that patients with post-index GI events were 34.6% less likely to receive BIS vs non-BIS as compared to patients without post-index GI events. CONCLUSION: Among women aged ≥ 55 years with an OP diagnosis, post-index GI events were associated with a lower likelihood of OP treatment initiation.

Early postpartum pumping behaviors, pumped milk volume, and achievement of secretory activation in breast pump-dependent mothers of preterm infants.

OBJECTIVE: Pumping studies in mothers of preterm infants are limited by self-reported pumping behaviors and non-objective measures of pumped milk volume and secretory activation (SA). METHODS: Non-randomized observational study of first 14 days postpartum in 29 mothers of preterm infants. Smart pumps measured and stored pumping behaviors and pumped milk volume. Selective ion electrodes measured sodium and sodium:potassium ratio to determine SA. Generalized estimating equations, cluster analyses and multivariate regression were used. RESULTS: SA was delayed (median 5.8 days) and impermanent. Each additional daily pumping increased odds of SA within 2 days by 48% (p = 0.01). High-intensity pumping mothers (N = 17) had greater daily and cumulative pumped milk volume than low-intensity pumping mothers (N = 12). Pumping variables showed daily changes in the first week, then plateaued. CONCLUSION: The first week postpartum is critical for optimizing pumping behaviors. Accurate, objective measures of pumping behaviors, pumped milk volume and SA are a research priority.

Early outcomes of moderate-to-high-risk pediatric congenital cardiac surgery and predictors of extracorporeal circulatory life support requirement.

Background: Cardiopulmonary failure refractory to medical management after moderate-to-high-risk congenital cardiac surgery may necessitate mechanical support with veno-arterial extracorporeal membrane oxygenation (ECMO). On the extreme, ECMO can also be initiated in the setting of cardiac arrest (extracorporeal cardiopulmonary resuscitation, ECPR) unresponsive to conventional resuscitative measures. Methods: This was a single-center retrospective cohort study of patients (n = 510) aged <3 years old who underwent cardiac surgery with cardiopulmonary bypass with a RACHS-1 score ≥3 between 2011 and 2014. Perioperative factors were reviewed to identify predictors of ECMO initiation and mortality in the operating room (OR) and the intensive care unit (ICU). Results: A total of 510 patients with a mean surgical age of 10.0 ± 13.4 months were included. Among them, 21 (4%) patients received postoperative ECMO-12 were initiated in the OR and 9 in the ICU. ECMO cannulation was associated with cardiopulmonary bypass duration, aortopulmonary shunt, residual severe mitral regurgitation, vaso-inotropic score, and postprocedural lactate (p < 0.001). Of the 32 (6%) total deaths, 7 (22%) were ECMO patients-4 were elective OR cannulations and 3 were ICU ECPR. Prematurity [hazard ratio (HR): 2.61, p < 0.01), Norwood or Damus-Kaye-Stansel procedure (HR: 4.29, p < 0.001), postoperative left ventricular dysfunction (HR: 5.10, p = 0.01), residual severe tricuspid regurgitation (HR: 6.06, p < 0.001), and postoperative ECMO (ECPR: HR: 15.42, p < 0.001 vs. elective: HR: 5.26, p = 0.01) were associated with mortality. The two patients who were electively cannulated in the ICU survived. Discussion: Although uncommon, postoperative ECMO in children after congenital cardiac surgery is associated with high mortality, especially in cases of ECPR. Patients with long cardiopulmonary bypass time, residual cardiac lesions, or increased vaso-inotropic requirement are at higher risk of receiving ECMO. Pre-emptive or early ECMO initiation before deterioration into cardiac arrest may improve survival.

Modeling the Relationship Between Diastolic Phenotype and Outcomes in Pediatric Hypertrophic Cardiomyopathy.

BACKGROUND: Pediatric hypertrophic cardiomyopathy (HCM) is associated with adverse events. The contribution of diastolic dysfunction to adverse events is poorly understood. The aim of this study was to explore the association between diastolic phenotype and outcomes in pediatric patients with HCM. METHODS: Children <18 years of age with diagnosed with HCM were included. Diastolic function parameters were measured from the first echocardiogram at the time of diagnosis, including Doppler flow velocities, tissue Doppler velocities, and left atrial volume and function. Using principal-component analysis, key features in echocardiographic parameters were identified. The principal components were regressed to freedom from major adverse cardiac events (MACE), defined as implantable cardioverter-defibrillator insertion, myectomy, aborted sudden cardiac death, transplantation, need for mechanical circulatory support, and death. RESULTS: Variables that estimate left ventricular filling pressures were highly collinear and associated with MACE (hazard ratio, 0.86; 95% CI, 0.75-1.00), though this was no longer significant after controlling for left ventricular thickness and genetic variation. Left atrial size parameters adjusted for body surface area were independently associated with outcomes in the covariate-adjusted model (hazard ratio, 0.69; 95% CI, 0.5-0.94). The covariate-adjusted model had an Akaike information criterion of 213, an adjusted R2 value of 0.78, and a concordance index of 0.82 for association with MACE. CONCLUSION: Echocardiographic parameters of diastolic dysfunction were associated with MACE in this population study, in combination with the severity of left ventricular hypertrophy and genetic variation. Left atrial size parameters adjusted for body surface area were independently associated with adverse events. Additional study of diastolic function parameters adjusted for patient size could facilitate the prediction of adverse events in pediatric patients with HCM.

Impact of Hemoglobin Level in Ex Vivo Heart Perfusion on Donation After Circulatory Death Hearts: A Juvenile Porcine Experimental Model.

BACKGROUND: Ex vivo heart perfusion (EVHP) of donation after circulatory death (DCD) hearts has become an effective strategy in adults; however, the small circulating volume in pediatrics poses the challenge of a low-hemoglobin (Hb) perfusate. We aimed to determine the impact of perfusate Hb levels during EVHP on DCD hearts using a juvenile porcine model. METHODS: Sixteen DCD piglet hearts (11-14 kg) were reperfused for 4 h in unloaded mode followed by working mode. Metabolism, cardiac function, and cell damage were compared between the low-Hb (Hb, 5.0-5.9 g/dL; n = 8) and control (Hb, 7.5-8.4 g/dL; n = 8) groups. Between-group differences were evaluated using 2-sample t-tests or Fisher's Exact tests. RESULTS: During unloaded mode, the low-Hb group showed lower myocardial oxygen consumption (P < 0.001), a higher arterial lactate level (P = 0.001), and worse systolic ventricular function (P < 0.001). During working mode, the low-Hb group had a lower cardiac output (mean, 71% versus 106% of normal cardiac output, P = 0.010) and a higher arterial lactate level (P = 0.031). Adjusted cardiac troponin-I (P = 0.112) did not differ between the groups. Morphological myocyte injury in the left ventricle was more severe in the low-Hb group (P = 0.028). CONCLUSIONS: Low-Hb perfusate with inadequate oxygen delivery induced anaerobic metabolism, resulting in suboptimal DCD heart recovery and declined cardiac function. Arranging an optimal perfusate is crucial to organ protection, and further endeavors to refine the priming volume of EVHP or the transfusion strategy are required.

Reimplantation of the aortic valve in patients with tricuspid aortic valve: the Toronto General Hospital experience.

Background: Aortic valve sparing operations were introduced three decades ago but controversy remains regarding its appropriateness, reproducibility and durability. This article describes the long-term outcomes of patients who had reimplantation of the aortic valve. Methods: All patients who had reimplantation of a tricuspid aortic valve at Toronto General Hospital from 1989 through 2019 were selected for this study. Patients were followed prospectively with periodical clinical assessments and imaging of the heart and aorta. Results: Four hundred and four patients were identified. The median age was 48.0 [interquartile range (IQR), 35.0-59.0] years and 310 (76.7%) were men. There were 150 patients with Marfan syndrome, 20 with Loeys-Dietz syndrome and 33 with acute or chronic aortic dissections. The median follow-up was 11.7 (IQR, 6.8-17.1) years. There were 55 patients alive and without reoperation at 20 years. The cumulative mortality at 20 years was 26.7% [95% confidence interval (CI): 20.6-34.2%], the cumulative incidence of reoperation on the aortic valve was 7.0% (95% CI: 4.0-12.2%) and the development of moderate or severe aortic insufficiency was 11.8% (95% CI: 8.5-16.5%). We could not identify variables associated with reoperation on the aortic valve or with the development of aortic insufficiency. New distal aortic dissections were common in patients with associated genetic syndromes. Conclusions: Reimplantation of the aortic valve in patients with tricuspid aortic valve provides excellent aortic valve function during the first two decades of follow-up. Distal aortic dissections are relatively common in patients with associated genetic syndromes.

Electromechanical Dyssynchrony Is Associated With Right Ventricular Remodeling and Dysfunction Independently of Pulmonary Regurgitation Late After Tetralogy of Fallot Repair.

BACKGROUND: The aim of this study was to investigate the relationship among right ventricular (RV) dilatation, dysfunction, and electromechanical dyssynchrony (EMD) in patients with repaired tetralogy of Fallot (rTOF). METHODS: Data from a prospective rTOF registry of subjects with moderate or greater pulmonary regurgitation (PR) and contemporary imaging were analyzed. Electrocardiograms and echocardiograms were analyzed for EMD (prolonged QRS duration [QRSd], echocardiographic septal flash, and mechanical delay) and mechanical dispersion. The relationship among these, RV measurements on cardiac magnetic resonance, exercise capacity, and incident arrhythmia or death was analyzed with adjustment for PR. RESULTS: In total, 271 patients with rTOF (42% women; median age, 32 years; interquartile range [IQR], 23-34 years) were included. Patients had moderate to severe PR (median PR fraction, 38%; IQR, 30%-47%), moderate to severe RV enlargement (median RV end-diastolic volume index, 161 mL/m2; IQR, 138-186 mL/m2) and mild RV systolic dysfunction (median RV ejection fraction [RVEF], 44%; IQR, 38%-48%). Eleven patients (4%) experienced ventricular arrhythmia or death. Presence of EMD was associated with larger RV size (RV end-diastolic volume index and RV end-systolic volume index, P = .006 and P < .001, respectively) and lower RVEF (P < .001). A sharp inflection in the relation among QRSd, RV size, and RVEF was observed when QRSd exceeded 150 msec (3.1% decrease in RVEF for every 20-msec increase in QRSd between 160 and 200 msec). Similar inflection points were observed for the mechanical delay between the RV basal-lateral and midseptal segments. The mechanical delay was higher in patients with vs without incident atrial arrhythmia (371 vs 276 msec, P = .014). CONCLUSIONS: In adults with rTOF, EMD is independently associated with larger RV size, lower RVEF, and incident atrial arrhythmias.

Maternal Anti-Ro Antibody Titers Obtained With Commercially Available Immunoassays Are Strongly Associated With Immune-Mediated Fetal Heart Disease.

OBJECTIVE: Anti-Ro antibody-positive mothers are frequently referred for serial echocardiography due to the fetal risk of developing heart block and endocardial fibroelastosis. Little is known why only some and not all offspring develop these cardiac manifestations of neonatal lupus (CNL). This prospective study examined associations between anti-Ro antibody titers and fetal CNL. METHODS: Antibody-positive mothers referred since 2018 for fetal echocardiography at risk of CNL (group 1; n = 240) or with CNL (group 2; n = 18) were included. Maternal antibody titers were measured with a chemiluminescent immunoassay (CIA). Additional testing on diluted serum samples was used to quantify anti-Ro 60 antibody titers above the analytical measuring range (AMR) of the standard CIA (≥1,375 chemiluminescent units [CU]). RESULTS: Among 27 total mothers with a fetal diagnosis of CNL, all displayed anti-Ro 60 antibody titers that exceeded the AMR of the CIA at least 10-fold. Of 122 mothers in group 1 who underwent additional anti-Ro 60 antibody testing, event rates of CNL (n = 9) were 0% (0 of 45) among mothers with anti-Ro 60 antibody titers from 1,375-10,000 CU, 5% (3 of 56) among mothers with titers from 10,000-50,000 CU, but 29% (6 of 21) among mothers with titers >50,000 CU (odds ratio 13.1, P = 0.0008). Of mothers in group 2 with a primary diagnosis of CNL, 0% (0 of 18 mothers) had anti-Ro 60 antibody titers <10,000 CU, 44% (8 of 18 mothers) had titers from 10,000-50,000 CU, and 56% (10 of 18 mothers) had titers >50,000 CU. CONCLUSION: CNL is associated with substantially higher anti-Ro antibody titers than are obtained using a standard CIA. Enhancing the assay measuring range allows an improved specificity of identifying pregnancies at risk of CNL.

Comprehensive Cardiovascular Magnetic Resonance Tissue Characterization and Cardiotoxicity in Women With Breast Cancer.

Importance: There is a growing interest in understanding whether cardiovascular magnetic resonance (CMR) myocardial tissue characterization helps identify risk of cancer therapy-related cardiac dysfunction (CTRCD). Objective: To describe changes in CMR tissue biomarkers during breast cancer therapy and their association with CTRCD. Design, Setting, and Participants: This was a prospective, multicenter, cohort study of women with ERBB2 (formerly HER2)-positive breast cancer (stages I-III) who were scheduled to receive anthracycline and trastuzumab therapy with/without adjuvant radiotherapy and surgery. From November 7, 2013, to January 16, 2019, participants were recruited from 3 University of Toronto-affiliated hospitals. Data were analyzed from July 2021 to June 2022. Exposures: Sequential therapy with anthracyclines, trastuzumab, and radiation. Main Outcomes and Measures: CMR, high-sensitivity cardiac troponin I (hs-cTnI), and B-type natriuretic peptide (BNP) measurements were performed before anthracycline treatment, after anthracycline and before trastuzumab treatment, and at 3-month intervals during trastuzumab therapy. CMR included left ventricular (LV) volumes, LV ejection fraction (EF), myocardial strain, early gadolinium enhancement imaging to assess hyperemia (inflammation marker), native/postcontrast T1 mapping (with extracellular volume fraction [ECV]) to assess edema and/or fibrosis, T2 mapping to assess edema, and late gadolinium enhancement (LGE) to assess replacement fibrosis. CTRCD was defined using the Cardiac Review and Evaluation Committee criteria. Fixed-effects models or generalized estimating equations were used in analyses. Results: Of 136 women (mean [SD] age, 51.1 [9.2] years) recruited from 2013 to 2019, 37 (27%) developed CTRCD. Compared with baseline, tissue biomarkers of myocardial hyperemia and edema peaked after anthracycline therapy or 3 months after trastuzumab initiation as demonstrated by an increase in mean (SD) relative myocardial enhancement (baseline, 46.3% [16.8%] to peak, 56.2% [18.6%]), native T1 (1012 [26] milliseconds to 1035 [28] milliseconds), T2 (51.4 [2.2] milliseconds to 52.6 [2.2] milliseconds), and ECV (25.2% [2.4%] to 26.8% [2.7%]), with P <.001 for the entire follow-up. The observed values were mostly within the normal range, and the changes were small and recovered during follow-up. No new replacement fibrosis developed. Increase in T1, T2, and/or ECV was associated with increased ventricular volumes and BNP but not hs-cTnI level. None of the CMR tissue biomarkers were associated with changes in LVEF or myocardial strain. Change in ECV was associated with concurrent and subsequent CTRCD, but there was significant overlap between patients with and without CTRCD. Conclusions and Relevance: In women with ERBB2-positive breast cancer receiving sequential anthracycline and trastuzumab therapy, CMR tissue biomarkers suggest inflammation and edema peaking early during therapy and were associated with ventricular remodeling and BNP elevation. However, the increases in CMR biomarkers were transient, were not associated with LVEF or myocardial strain, and were not useful in identifying traditional CTRCD risk.

Evaluation of Risk Prediction Models to Identify Cancer Therapeutics Related Cardiac Dysfunction in Women with HER2+ Breast Cancer.

Cancer-therapeutics-related cardiac dysfunction (CTRCD) is an important concern in women receiving trastuzumab therapy for HER2+ breast cancer. However, the ability to assess CTRCD risk remains limited. In this retrospective cohort study, we apply three published risk prediction models (Ezaz et al., NSABP-31 cardiac risk scores (CRS), and HFA-ICOS trastuzumab proforma) to 629 women (mean age 52.4 ± 10.9 years) with Stage I-III HER2+ breast cancer treated with trastuzumab ± anthracyclines to assess their performance to identify CTRCD during or immediately post treatment. Using these models, patients were classified into CTRCD risk categories according to the pre-treatment characteristics. With NSABP-31 CRS and HFA-ICOS proformas, patients in the highest risk category had a 1.7-to-2.4-fold higher relative risk of CTRCD than the low-risk category (p = 0.010 and 0.005, respectively). However, with all three risk models, those in the low-risk category had a high absolute risk of CTRCD (15.5-25.5%). The discrimination of the models for CTRCD (AUC 0.51-0.60) and their calibration was limited. NSAP-31 CRS and HFA-ICOS proformas can identify relative differences in CTRCD risk between patients, but when considering absolute risk, they are only able to identify the highest risk patients. There remains an ongoing need for accurate CTRCD risk prediction models in women with HER2+ breast cancer.

Closure of Left Atrial Appendage Has no Effect on Thromboembolic Rates after Mitral Valve Repair in Patients in Sinus Rhythm.

Closure of the left atrial appendage (LAA) reduces the rates of TIA/stroke in patients in atrial fibrillation (AF) but its role in patients in sinus rhythm who undergo mitral valve repair (MV) for leaflet prolapse remains unknown. This study examined the effects of closing the LAA in TIA/stroke after MV repair. Our database on patients who had MV repair for leaflet prolapse from 2000 through 2019 was reviewed. After excluding patients at higher risk of TIA/stroke, 1050 patients in sinus rhythm were entered into the study: 781 with open LAA and 269 with surgically closed LAA. Using a propensity score analysis to compensate from clinical differences, 267 pairs of patients with open and closed LAA were matched. Follow-up was truncated at 5 years because routine closure of the LAA was performed only during recent years. The cumulative incidence of TIA/stroke at 5 years in the entire cohort was 2.7% [95% CI 1.9, 4.0]; it was 2.9% [95% CI 1.9, 4.4] in patients with open LAA,and 1.8% [95% CI 0.7, 4.9] in patients with closed LAA (P = 0.53). In the matched cohorts, the cumulative incidences of TIA/stroke did not differ significantly (match-adjusted HR [95% CI] = 0.80 [0.21, 2.98], P = 0.74), and multivariable Cox proportional hazard regression analysis also confirmed no difference in the risk of TIA/stroke between the 2 groups (regression-adjusted HR [95% CI] = 0.58 [0.12, 2.9], P = 0.47). This study failed to show a reduction in the risk of TIA/stroke by closing the LAA in patients in sinus rhythm (Figure 6). Closure of the LAA during MV repair warrants a larger and more rigorous study.

Self-Reported Physical Activity, QoL, Cardiac Function, and Cardiorespiratory Fitness in Women With HER2+ Breast Cancer.

Background: Women treated for breast cancer are at risk for worsening health-related quality of life (QoL), cardiac function, and cardiorespiratory fitness. Objectives: The aim of this study was to assess the associations of self-reported moderate to vigorous intensity physical activity (MVPA) during cancer treatment with concurrent measures of QoL and cardiac function and with post-treatment cardiorespiratory fitness in women with human epidermal growth factor receptor 2-positive breast cancer receiving sequential anthracyclines and trastuzumab. Methods: EMBRACE-MRI 1 (Evaluation of Myocardial Changes During Breast Adenocarcinoma Therapy to Detect Cardiotoxicity Earlier With MRI) study participants who completed questionnaires for MVPA (modified Godin Leisure Time Physical Activity Questionnaire) and QoL (EQ-5D-3L, Minnesota Living With Heart Failure Questionnaire) and cardiac imaging every 3 months during treatment and post-treatment cardiopulmonary exercise testing were included. Participants engaging in ≥90 minutes of MVPA each week were labeled "active." Generalized estimation equations and linear regression analyses were used to assess concurrent and post-treatment associations with MVPA and activity status, respectively. Results: Eighty-eight participants were included (mean age 51.4 ± 8.9 years). Mean MVPA minutes, QoL, and cardiac function (left ventricular ejection fraction, global longitudinal strain, E/A ratio, and E/e' ratio) worsened by 6 months into trastuzumab therapy. Higher MVPA (per 30 minutes) during treatment was associated with better concurrent overall (ß = -0.42) and physical (ß = -0.24) Minnesota Living With Heart Failure Questionnaire scores, EQ-5D-3L index (ß = 0.003), visual analogue scale score (ß = 0.43), diastolic function (E/A ratio; ß = 0.01), and global longitudinal strain (ß = 0.04) at each time point (P ≤ 0.01 for all). Greater cumulative MVPA over the treatment period was associated with higher post-treatment cardiorespiratory fitness (peak oxygen consumption; ß = 0.06 per 30 minutes; P < 0.001). Conclusions: Higher self-reported MVPA during treatment for human epidermal growth factor receptor 2-positive breast cancer was associated with better QoL and diastolic and systolic left ventricular function measures during treatment and better post-treatment cardiorespiratory fitness.

A Combined Echocardiography Approach for the Diagnosis of Cancer Therapy-Related Cardiac Dysfunction in Women With Early-Stage Breast Cancer.

IMPORTANCE: Diagnosis of cancer therapy-related cardiac dysfunction (CTRCD) remains a challenge. Cardiovascular magnetic resonance (CMR) provides accurate measurement of left ventricular ejection fraction (LVEF), but access to repeated scans is limited. OBJECTIVE: To develop a diagnostic model for CTRCD using echocardiographic LVEF and strain and biomarkers, with CMR as the reference standard. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, patients were recruited from University of Toronto-affiliated hospitals from November 2013 to January 2019 with all cardiac imaging performed at a single tertiary care center. Women with human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer were included. The main exclusion criterion was contraindication to CMR. A total of 160 patients were recruited, 136 of whom completed the study. EXPOSURES: Sequential therapy with anthracyclines and trastuzumab. MAIN OUTCOMES AND MEASURES: Patients underwent echocardiography, high-sensitivity troponin I (hsTnI), B-type natriuretic peptide (BNP), and CMR studies preanthracycline and postanthracycline every 3 months during and after trastuzumab therapy. Echocardiographic measures included 2-dimensional (2-D) LVEF, 3-D LVEF, peak systolic global longitudinal strain (GLS), and global circumferential strain (GCS). LVEF CTRCD was defined using the Cardiac Review and Evaluation Committee Criteria, GLS or GCS CTRCD as a greater than 15% relative change, and abnormal hsTnI and BNP as greater than 26 pg/mL and ≥ 35 pg/mL, respectively, at any follow-up point. Combinations of echocardiographic measures and biomarkers were examined to diagnose CMR CTRCD using conditional inference tree models. RESULTS: Among 136 women (mean [SD] age, 51.1 [9.2] years), CMR-identified CTRCD occurred in 37 (27%), and among those with analyzable images, in 30 of 131 (23%) by 2-D LVEF, 27 of 124 (22%) by 3-D LVEF, 53 of 126 (42%) by GLS, 61 of 123 (50%) by GCS, 32 of 136 (24%) by BNP, and 14 of 136 (10%) by hsTnI. In isolation, 3-D LVEF had greater sensitivity and specificity than 2-D LVEF for CMR CTRCD while GLS had greater sensitivity than 2-D or 3-D LVEF. Regression tree analysis identified a sequential algorithm using 3-D LVEF, GLS, and GCS for the optimal diagnosis of CTRCD (area under the receiver operating characteristic curve, 89.3%). The probability of CTRCD when results for all 3 tests were negative was 1.0%. When 3-D LVEF was replaced by 2-D LVEF in the model, the algorithm still performed well; however, its primary value was to rule out CTRCD. Biomarkers did not improve the ability to diagnose CTRCD. CONCLUSIONS AND RELEVANCE: Using CMR CTRCD as the reference standard, these data suggest that a sequential approach combining echocardiographic 3-D LVEF with 2-D GLS and 2-D GCS may provide a timely diagnosis of CTRCD during routine CTRCD surveillance with greater accuracy than using these measures individually. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02306538.

Sparing the Prod: Providing an Alternative to Endomyocardial Biopsies With Noninvasive Surveillance After Heart Transplantation During COVID-19.

Background: The COVID-19 pandemic has reduced access to endomyocardial biopsy (EMB) rejection surveillance in heart transplant (HT) recipients. This study is the first in Canada to assess the role for noninvasive rejection surveillance in personalizing titration of immunosuppression and patient satisfaction post-HT. Methods: In this mixed-methods prospective cohort study, adult HT recipients more than 6 months from HT had their routine EMBs replaced by noninvasive rejection surveillance with gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) testing. Demographics, outcomes of noninvasive surveillance score, hospital admissions, patient satisfaction, and health status on the medical outcomes study 12-item short-form health survey (SF-12) were collected and analyzed, using t tests and χ2 tests. Thematic qualitative analysis was performed for open-ended responses. Results: Among 90 patients, 31 (33%) were enrolled. A total of 36 combined GEP/dd-cfDNA tests were performed; 22 (61%) had negative results for both, 10 (27%) had positive GEP/negative dd-cfDNA results, 4 (11%) had negative GEP/positive dd-cfDNA results, and 0 were positive on both. All patients with a positive dd-cfDNA result (range: 0.19%-0.81%) underwent EMB with no significant cellular or antibody-mediated rejection. A total of 15 cases (42%) had immunosuppression reduction, and this increased to 55% in patients with negative concordant testing. Overall, patients' reported satisfaction was 90%, and on thematic analysis they were more satisfied, with less anxiety, during the noninvasive testing experience. Conclusions: Noninvasive rejection surveillance was associated with the ability to lower immunosuppression, increase satisfaction, and reduce anxiety in HT recipients, minimizing exposure for patients and providers during a global pandemic.

Contexte: La pandémie de COVID-19 a réduit l'accès à la biopsie endomyocardique pour surveiller le risque de rejet après une greffe du cœur. Cette étude est la première à être menée au Canada pour évaluer le rôle de la surveillance non invasive du risque de rejet en personnalisant le titrage de l'immunosuppression et la satisfaction du patient après la greffe cardiaque. Méthodologie: Dans le cadre de cette étude de cohorte prospective à méthodes mixtes, des adultes ayant reçu une greffe cardiaque depuis plus de six mois ont vu leurs biopsies endomyocardiques régulières remplacées par une surveillance non invasive du risque de rejet qui consiste à établir le profil de l'expression génique et à analyser l'ADN acellulaire dérivé du donneur. Les données démographiques, les résultats du score de surveillance non invasive, les admissions à l'hôpital, la satisfaction des patients et l'état de santé tirés du questionnaire SF-12 (questionnaire abrégé sur la santé comprenant 12 items) de l'étude sur les issues médicales ont été colligés et analysés au moyen des tests T et des tests χ2. Les réponses ouvertes ont fait l'objet d'une analyse qualitative thématique. Résultats: Parmi 90 patients, 31 (33 %) ont été recrutés. Au total, 36 tests combinés de profilages de l'expression génique et d'ADN acellulaire dérivé du donneur ont été réalisés; les résultats ont été négatifs pour les deux tests dans 22 cas (61 %), positifs pour le profilage de l'expression génique et négatifs pour l'ADN acellulaire dans 10 cas (27 %), négatifs pour le profilage de l'expression génique et positifs pour l'ADN acellulaire dans quatre cas (11 %) et aucun cas n'a donné de résultats positifs pour les deux types de tests. Tous les patients qui ont donné des résultats positifs à l'analyse de l'ADN acellulaire dérivé du donneur (fourchette : 0,19 % à 0,81 %) ont subi une biopsie endomyocardique n'ayant révélé aucun rejet cellulaire ou à médiation par anticorps important. Au total, 15 cas (42 %) affichaient une immunosuppression réduite, proportion qui a grimpé à 55 % chez les patients dont les tests de concordance ont donné des résultats négatifs. Dans l'ensemble, le niveau de satisfaction rapporté par les patients était de 90 % et, à l'analyse thématique, ils étaient plus satisfaits et moins anxieux pendant les tests non invasifs. Conclusions: La surveillance non invasive du risque de rejet a été associée à la capacité de diminuer l'immunosuppression, d'augmenter la satisfaction et de réduire l'anxiété chez les patients qui ont reçu une greffe cardiaque, en plus de réduire l'exposition des patients et du personnel médical dans le contexte d'une pandémie.

Compliance, persistence, healthcare resource use, and treatment costs associated with aliskiren plus ARB versus ACE inhibitor plus ARB combination therapy: in US patients with hypertension.

BACKGROUND: Evidence is currently equivocal on the added benefits of dual blockade of the renin-angiotensin-aldosterone system with the combination of either an ACE inhibitor (ACEI) plus an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) or aliskiren, the first-in-class direct renin inhibitor, plus an ARB. OBJECTIVE: To compare the compliance, persistence, healthcare resource utilization, and healthcare costs associated with aliskiren plus ARB versus ACEI plus ARB combination therapies among adult patients diagnosed with hypertension. METHODS: Patients (aged ≥18 years) initiated on either combination therapy were identified in the MarketScan Commercial and Medicare Supplemental Databases (1 July 2007 to 30 June 2008). The ARB components considered were candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. The ACEI components included benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. Outcomes measured during the 6-month study period included the proportion of days covered (PDC), treatment discontinuation, healthcare resource utilization, and changes in healthcare costs (study period minus 6-month baseline values). Risk-adjusted differences in outcomes between treatments and associated 95% confidence intervals (CIs) were estimated using multivariate regression models, controlling for demographics, region, co-morbidities, prescription drug use, and resource utilization during the baseline period. RESULTS: Adjusting for baseline characteristics, aliskiren plus ARB patients (n = 1395) demonstrated a significantly higher PDC (67.0% vs 54.3%; difference 12.7%; 95% CI 10.6, 14.7) and a significantly lower discontinuation rate (50.4% vs 68.6%; odds ratio 0.46; 95% CI 0.40, 0.54) than ACEI plus ARB patients (n = 16 507). Aliskiren plus ARB patients had significantly fewer all-cause hospitalizations (adjusted incidence rate ratio [IRR] 0.73; 95% CI 0.61, 0.86) and significantly fewer all-cause emergency room (ER) visits (adjusted IRR 0.72; 95% CI 0.61, 0.85) than ACEI plus ARB patients. Compared with ACEI plus ARB therapy, aliskiren plus ARB therapy was associated with significantly larger increases in prescription costs by $US264 post therapy initiation (95% CI 153, 375), but with non-significantly greater reductions in total healthcare costs by -$583 (95% CI -2409, 1242).[2008 values]. CONCLUSION: In adult hypertensive patients, treatment with aliskiren plus ARB was associated with significantly better compliance/persistence and fewer hospitalizations and ER visits compared with ACEI plus ARB therapy. Reductions in total healthcare costs were non-significantly different between patients treated with aliskiren plus ARB versus ACEI plus ARB, despite the increased prescription costs associated with aliskiren plus ARB therapy.

Risk factors for postoperative hyperglycemia in neonates.

OBJECTIVE: Postoperative hyperglycemia has been shown to be associated with higher morbidity and mortality in pediatric patients. Data on risk factors for neonatal patients is limited. The objective of this study was to identify pre- and intraoperative risk factors associated with postoperative glucose in neonates. METHODS: We conducted a retrospective cohort study of neonates after surgical procedures between January and December 2016 in a quaternary neonatal intensive care unit. The primary outcome was hyperglycemia defined as serum glucose ≥8.3 mmol/L during the first 4 hours postoperatively. Secondary outcomes included death and length of stay. We assessed the association of risk factors with the postoperative glucose. RESULTS: In total, 206 surgical procedures (171 patients) were evaluated, among which 178 had serum glucose values during the first 4 hours postoperatively available. The incidence of hyperglycemia was 54% (n = 96). The median (IQR) glucose during the first 4 hours in NICU was 8.4 (6.52-10.65) mmol/L. Risk factors for postoperative hyperglycemia were intraoperative glucose infusion rate (GIR) and gestational age. There was a non-linear relationship between gestational age and postoperative hyperglycemia. Mortality occurred in 6 (7%) in the no-hyperglycemia group and 3 (3%) in the hyperglycemia group (p = 0.31). CONCLUSIONS: Among the risk factors, intraoperative GIR was identified as a modifiable factor that can reduce postoperative hyperglycemia. A non-linear relationship of gestational age with postoperative glucose provides new insights that may help advance our understanding of the complex mechanisms of glucose homeostasis in neonates.