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Purpose: The magnitude of cardiorespiratory fitness (CRF) impairment during anticancer treatment and CRF response to aerobic exercise training (AT) are highly variable. The aim of this ancillary analysis was to leverage machine learning approaches to identify patients at high risk of impaired CRF and poor CRF response to AT., Methods: We evaluated heterogeneity in CRF among 64 women with metastatic breast cancer randomly assigned to 12 weeks of highly structured AT (n = 33) or control (n = 31). Unsupervised hierarchical cluster analyses were used to identify representative variables from multidimensional prerandomization (baseline) data, and to categorize patients into mutually exclusive subgroups (ie, phenogroups). Logistic and linear regression evaluated the association between phenogroups and impaired CRF (ie, ≤16 mL O 2 ·kg -1 ·min -1 ) and CRF response., Results: Baseline CRF ranged from 10.2 to 38.8 mL O 2 ·kg -1 ·min -1 ; CRF response ranged from -15.7 to 4.1 mL O 2 ·kg -1 ·min -1 . Of the n = 120 candidate baseline variables, n = 32 representative variables were identified. Patients were categorized into two phenogroups. Compared with phenogroup 1 (n = 27), phenogroup 2 (n = 37) contained a higher number of patients with none or >three lines of previous anticancer therapy for metastatic disease and had lower resting left ventricular systolic and diastolic function, cardiac output reserve, hematocrit, lymphocyte count, patient-reported outcomes, and CRF ( P < .05) at baseline. Among patients allocated to AT (phenogroup 1, n = 12; 44%; phenogroup 2, n = 21; 57%), CRF response (-1.94 ± 3.80 mL O 2 ·kg -1 ·min -1 v 0.70 ± 2.22 mL O 2 ·kg -1 ·min -1 ) was blunted in phenogroup 2 compared with phenogroup 1., Conclusion: Phenotypic clustering identified two subgroups with unique baseline characteristics and CRF outcomes. The identification of CRF phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions among patients with cancer.

Background: Implantable cardioverter-defibrillator (ICD) shocks are a common complication following Left Ventricular Assist Device (LVAD) implantation; however, there is limited data on their frequency and causes., Objective: To define the incidence, programming, patient characteristics, and factors associated with appropriate and inappropriate ICD shocks in persons with LVADs., Methods: We performed a retrospective review at Duke University Hospital of all LVAD recipients implanted between January 1, 2013 to June 30, 2019 with a pre-existing ICD. ICD shocks were adjudicated by the treating physician and a 2 nd reviewer for the purpose of this study., Results: Among 421 patients with an ICD in situ undergoing LVAD implant, 147 (33.9%) patients had at least one shock following LVAD implantation. Among 134 patients with complete device history, there were a total of 330 shock episodes: 255 (77.3%) appropriate and 75 (22.7%) inappropriate. Etiologies for inappropriate shocks included SVT (n=66, 20.0%), physiologic oversensing (n=1, 0.3%), and non-physiologic oversensing (n=8, 2.4%) including LVAD electromagnetic interference (n=1, 0.3%). ICD programming with shorter detection delay (p < 0.001) and absence of anti-tachycardia pacing programming (p = 0.001) in high-rate zones was seen more commonly in inappropriate shock than appropriate shock., Conclusions: The rate of inappropriate shocks in LVAD recipients is very high and is most often due to supraventricular arrhythmias. LVAD electromagnetic interference is a rare cause of ICD shock. Implementation of current consensus AHA recommendations for LVAD programming with long detection delays and high rate cutoffs may help avoid inappropriate ICD shocks., (Copyright © 2024. Published by Elsevier Inc.)

Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments., Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population., Design, Setting, and Participants: A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024., Exposure: V142I carrier status (n = 754, 3.2%)., Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data., Results: Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant., Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

Competing Interests: Dr Karra has received institutional research support from Alnylam Pharmaceuticals and Intellia Therapeutics; and is a member of Alnylam Pharmaceuticals Speakers Bureau. Dr Costa Chase has received institutional research support from GlaxoSmithKline; and speaks on behalf of Sanofi. Dr Khouri has received institutional research support from Pfizer, BridgeBio Pharma, Alnylam Pharmaceuticals, and Ionis Pharmaceuticals; has received consulting/advisory board support from BridgeBio Pharma and Alnylam Pharmaceuticals; and is a member of Alnylam Pharmaceuticals Speakers Bureau. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: CARS (Cardiac Amyloidosis Registry Study) is a multicenter registry established in 2019 that includes patients with transthyretin (ATTR, wild-type and variant) and light chain (AL) cardiac amyloidosis (CA) evaluated at major amyloidosis centers between 1997 and 2025. CARS aims to describe the natural history of CA with attention to clinical and diagnostic variables at the time of diagnosis, real-world treatment patterns, and associated outcomes of patients in a diverse cohort that is more representative of the at-risk population than that described in CA clinical trials., Methods and Results: This article describes the design and methodology of CARS, including procedures for data collection and preliminary results. As of February 2023, 20 centers in the United States enrolled 1415 patients, including 1155 (82%) with ATTR and 260 (18%) with AL CA. Among those with ATTR, wild-type is the most common ATTR (71%), and most of the 305 patients with variant ATTR have the p.V142I mutation (68%). A quarter of the total population identifies as Black. More individuals with AL are female (39%) compared to those with ATTR (13%)., Conclusions: CARS will answer crucial clinical questions about CA natural history and permit comparison of different therapeutics not possible through current clinical trials. Future international collaboration will further strengthen the validity of observations of this increasingly recognized condition., Competing Interests: Disclosures JLG reports consulting fees from Pfizer, Eidos/BridgeBio, Alnlyam, Intellia, Sarepta, and AstraZeneca; Grant support from Pfizer 67656485, Eidos/BridgeBio, Texas Health Resources Clinical Scholarship, and NHLBI R01 HL160892-01A1. MSM reports consulting fees from AstraZeneca, Akcea, Intellia, and Novo-Nordisk; grant support from NIH R01HL139671, Alnylam, Pfizer, Eidos, Prothena, and Ionis. FLR reports consulting fees from Attralus and grant support from Pfizer, Alnylam, and Akcea/Ionis. ARP reports grant support from Pfizer. MGK reports consulting fees from and advisory board membership in Pfizer, Eidos, Alnylam; Grant support: Pfizer, Alnylam, Eidos, Ionis, and Moleculin Biotech and speaker's bureau with Alnylam. YB reports grant support from Pfizer. BMD reports consulting fees from Anylam and Eidos. NMF reports consulting/speaker's fees and bureau/honoraria from Pfizer, Akcea/Ionis, Sobi, Alnylam, Sanofi-Genzyme, AstraZeneca, and Takeda; grant support from Pfizer, Akcea/Ionis, Servier, Takeda, Novartis, and Eidos. HG reports consulting fees from Amgen, Bayer, Merck, Pfizer, and ExpertConnect and grant support from Roche Diagnostics, Jana Care, Ortho Clinical, Novartis, Pfizer, Alnylam, Akcea/Ionis, and Eidos/BridgeBio and stock ownership in Eko; research payments for clinical endpoint committees from Baim INstitute for Clinical Research for Abbott, Siemens and Beckman Coulter and from ACI Clinical for Abbott Laboratories. DJ reports consulting fees from Alexion, Alleviant, Cytokinetics, Novo-Nordisk, Pfizer, Renovacor/Rocket, and Tenaya. JM reports consultingfees from Myocardial Solutions, Abbott, Longer Life Foundation, Children's Discovery Institue, Pfizer, BridgeBio, and Altathera. SSM reports speaker's fees from and Bureau/Advisory Board member of Alnylam. RCM reports consulting fees/honoraria from Pfizer and AstraZeneca. FHS reports grant support from Alnylam and Ionis. BS reports consulting fees from Alnylam and BridgeBio/Eidos and speaker's bureau fees from Pfizer. MU reports grant support from Ionis; advisory board membership with Alnylam, Cytokinetics, BridgeBio/Eidos; speaker's bureau with Pfizer, Alnylam, Akcea. JKP reports grant support from Alexion, Alnylam, AstraZeneca, BridgeBio/Eidos, Novo-Nordisk, and Pfizer; advisory board/speaker's bureau membership with Alnylam, CareDx, Eidos, Ionis, Natera, and Pfizer. All other authors have no financial relationships to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Background: An 11-factor random forest model has been developed among ambulatory heart failure (HF) patients for identifying potential wild-type amyloidogenic TTR cardiomyopathy (wtATTR-CM). The model has not been evaluated in a large sample of patients hospitalized for HF., Methods: This study included Medicare beneficiaries aged ≥65 years hospitalized for HF in the Get With The Guidelines-HF® Registry from 2008-2019. Patients with and without a diagnosis of ATTR-CM were compared, as defined by inpatient and outpatient claims data within 6 months pre- or post-index hospitalization. Within a cohort matched 1:1 by age and sex, univariable logistic regression was used to evaluate relationships between ATTR-CM and each of the 11 factors of the established model. Discrimination and calibration of the 11-factor model were assessed., Results: Among 205,545 patients (median age 81 years) hospitalized for HF across 608 hospitals, 627 patients (0.31%) had a diagnosis code for ATTR-CM. Univariable analysis within the 1:1 matched cohort of each of the 11-factors in the ATTR-CM model found pericardial effusion, carpal tunnel syndrome, lumbar spinal stenosis, and elevated serum enzymes (e.g., troponin elevation) to be strongly associated with ATTR-CM. The 11-factor model showed modest discrimination (c-statistic 0.65) and good calibration within the matched cohort., Conclusions: Among US patients hospitalized for HF, the number of patients with ATTR-CM defined by diagnosis codes on an inpatient/outpatient claim within 6 months of admission was low. Most factors within the prior 11-factor model were associated with greater odds of ATTR-CM diagnosis. In this population, the ATTR-CM model demonstrated modest discrimination., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Increased myocardial stiffness (MS) is an important hallmark of cardiac amyloidosis (CA) caused by myocardial amyloid deposition. Standard echocardiography metrics assess MS indirectly via downstream effects of cardiac stiffening. The ultrasound elastography methods acoustic radiation force impulse (ARFI) and natural shear wave (NSW) imaging assess MS more directly., Methods: This study compared MS in 12 healthy volunteers and 13 patients with confirmed CA using ARFI and NSW imaging. Parasternal long-axis acquisitions of the interventricular septum were obtained using a modified Acuson Sequoia scanner and a 5V1 transducer. ARFI-induced displacements were measured through the cardiac cycle, and ratios of diastolic-over-systolic displacement were calculated. NSW speeds from aortic valve closure were extracted from echocardiography-tracked displacement data., Results: ARFI stiffness ratios were significantly lower in CA patients than controls (mean ± standard deviation: 1.47 ± 0.27 vs. 2.10 ± 0.47, p < 0.001), and NSW speeds were significantly higher in CA patients than controls (5.58 ± 1.10 m/s vs. 3.79 ± 1.10 m/s, p < 0.001). A linear combination of the two metrics exhibited greater diagnostic potential than either metric alone (area under the curve = 0.97 vs. 0.89 and 0.88)., Conclusion: MS was measured to be significantly higher in CA patients using both ARFI and NSW imaging. Together, these methods have potential utility to aid in clinical diagnosis of diastolic dysfunction and infiltrative cardiomyopathies., Competing Interests: Conflict of interest J.K. is a speaker and consultant for Philips and GE. M.K. reports research support from Pfizer, Alnylam Pharmaceuticals, Eidos Therapeutics and Boston Scientific and consulting/advisory board support from Pfizer, Alnylam Pharmaceuticals and Eidos Therapeutics, and is a member of Alnylam Pharmaceuticals Speaker's Bureau. G.E.T. reports a financial interest in Samsung Inc., which is developing products related to the research described in this article; he has intellectual property in acoustic radiation force impulse (ARFI) and shear wave elasticity imaging. His laboratory at Duke University has a master research agreement with Siemens Medical Solutions USA, Inc. In this work ARFI imaging is described in an implementation that is not U.S. Food and Drug Administration cleared for clinical use. The other authors report no disclosures., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

There are nearly 17 million cancer survivors in the United States, including those who are currently receiving cancer therapy with curative intent and expected to be long-term survivors, as well as those with chronic cancers such as metastatic disease or chronic lymphocytic leukemia, who will receive cancer therapy for many years. Current clinical practice guidelines focus on lifestyle interventions, such as exercise and healthy eating habits, but generally do not address management strategies for clinicians or strategies to increase adherence to medications. We discuss 3 cardiometabolic comorbidities among cancer survivors and present the prevalence of comorbidities prior to a cancer diagnosis, treatment of comorbidities during cancer therapy, and management considerations of comorbidities in long-term cancer survivors or those on chronic cancer therapy. Approaches to support medication adherence and potential methods to enhance a team approach to optimize care of the individual with cancer across the continuum of disease are discussed., Competing Interests: This work was supported by a grant from the National Cancer Institute (CA249568; MPI Drs Oeffinger and Zullig). Dr Zullig has received research funding from Proteus Digital Health and the PhRMA Foundation; and consulting fees from Novartis and Pfizer. Dr Sung has received research grants from Merck and Novartis; and research supplies from DSM and Clasado. Dr Blalock has served as a consultant for the Eating Recovery Center. Dr Bosworth has received research grants from the PhRMA Foundation, Proteus Digital Health, Otsuka, Novo Nordisk, Sanofi, and Improved Patient Outcomes; and consulting fees from Sanofi, Novartis, Otsuka, Abbott, Preventric Diagnostics, and the Medicines Company. Dr Oeffinger has served as a consultant for GRAIL. Dr Dent has received honoraria and grant funding from Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSI) are associated with deleterious physical effects, which exercise may mitigate; however, exercise has never been studied in patients initiating treatment with ADT and an ARSI. Our objective was to determine whether supervised exercise prior to and during initial therapy could mitigate adverse effects of ADT plus enzalutamide., Methods: We conducted a single center trial in patients with recurrent prostate cancer treated with ADT and enzalutamide. We randomized 26 patients to 16 weeks of supervised exercise (aerobic and resistance), starting 4 weeks before initiation of ADT and enzalutamide, or usual care. The primary endpoint was change in peak oxygen uptake (VO 2 peak) as a measure of cardiorespiratory fitness (CRF). Secondary endpoints were functional capacity, maximal strength, body composition, patient-reported outcomes, safety, and feasibility. Analysis of covariance was used to compare outcomes for groups at Week 17 adjusted for baseline values., Results: The usual care group (N = 13) showed declines from baseline to week 17 in both absolute CRF (-0.31 L/min, -10.9%; p < 0.01) and relative CRF (-3.2 mL/kg/min, -8.9%; p = 0.04); worse fatigue (p = 0.01); and worse quality of life (p = 0.01). At week 17, the exercise group (N = 13) demonstrated improved absolute CRF (between-group change +0.20 L/min, p = 0.05), leg strength (+48.6 kg, p < 0.01) and functional capacity (+21.0 m, p = 0.01) at week 17., Conclusions: This is the first randomized controlled trial demonstrating a clinically significant decline in CRF in patients initiating ADT and enzalutamide. We show the effectiveness of short-term supervised exercise to mitigate declines in absolute CRF, and improve maximal leg strength and functional capacity., Gov Identifier: NCT02256111., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Ventricular arrhythmias (VAs) and electrical storm (ES) are recognized complications following left ventricular assist device (LVAD) implantation; however, their association with long term-outcomes remains poorly understood., Objective: The purpose of this study was to describe the clinical impact of ES in a population of patients undergoing LVAD implantation at a quaternary care center in the United States., Methods: This was an observational retrospective study of patients undergoing LVAD implantation from 2009 to 2020 at Duke University Hospital. The incidence of ES (≥3 sustained VA episodes over a 24-hour period without an identifiable reversible cause) was determined from patient records. Risk factors for ES were identified using multivariable Cox proportional hazards modeling., Results: Among 730 patients undergoing LVAD implant, 78 (10.7%) developed ES at a median of 269 (interquartile range [IQR] 7-766) days following surgery. Twenty-seven patients (34.6%) developed ES within 30 days, while 51 (65.4%) presented with ES at a median 639 (IQR 281-1017) days after implant. Following ES, 41% of patients died within 1 year. Patients who developed ES were more likely to have a history of VAs, ventricular tachycardia ablation, antiarrhythmic drug use, and perioperative mechanical circulatory support around the time of LVAD implant than patients without ES., Conclusion: ES occurs in 1 in 10 patients after LVAD and is associated with higher mortality. Risk factors for ES include a history of VAs, VT ablation, antiarrhythmic drug use, and perioperative mechanical circulatory support. Optimal management of ES surrounding LVAD implant, including escalation of medical therapy, catheter ablation, or adjunctive sympatholytic therapies, remains uncertain., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac amyloidosis is a progressive infiltrative disease involving deposition of amyloid fibrils in the myocardium and cardiac conduction system that frequently manifests with heart failure (HF) and arrhythmias, most frequently atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT)., Methods: We performed an observational retrospective study of patients with a diagnosis of cardiac amyloid who underwent catheter ablation at our institution between January 1, 2011 and December 1, 2018. Patient demographics, procedural characteristics, and outcomes were determined by manual chart review., Results: A total of 13 catheter ablations were performed over the study period in patients with cardiac amyloidosis, including 10 AT/AF/AFL ablations and three atrioventricular nodal ablations. Left ventricular ejection fraction was lower at the time of AV node ablation than catheter ablation of AT/AF/AFL (23% vs 40%, P = .003). Cardiac amyloid was diagnosed based on the results of preablation cardiac MRI results in the majority of patients (n = 7, 70%). The HV interval was prolonged at 60 ± 15 ms and did not differ significantly between AV nodal ablation patients and AT/AF/AFL ablation patients (69 ± 18 ms vs 57 ± 14 ms, P = .36). The majority of patients undergoing AT/AF/AFL ablation had persistent AF (n = 7, 70%) and NYHA class II (n = 5, 50%) or III (n = 5, 50%) HF symptoms, whereas patients undergoing AV node ablation were more likely to have class IV HF (n = 2, 66%, P = .014). Arrhythmia-free survival in CA patients after catheter ablation of AT/AF/AFL was 40% at 1 year and 20% at 2 years., Conclusions: Catheter ablation of AT/AF/AFL may be a feasible strategy for appropriately selected patients with early to mid-stage CA, whereas AV node ablation may be more appropriate in patients with advanced-stage CA., (© 2020 Wiley Periodicals LLC.)

Objectives: This study characterized the relationship between conduction disease and cardiac amyloidosis (CA) through longitudinal analysis of cardiac implantable electronic device (CIED) data., Background: Bradyarrhythmias and tachyarrhythmias are commonly reported in CA and may precede a CA diagnosis, although the natural history of conduction disease in CA is not well-described., Methods: Patients with CA (transthyretin amyloidosis cardiomyopathy [ATTR-CM] and light-chain amyloidosis [AL-CA]) and a CIED were identified within the Duke University Health System. Patient characteristics at the time of implantation, including demographics and data relevant to CA diagnosis, cardiac imaging, and CIED were recorded. CIED interrogations were analyzed for pacing and atrial fibrillation (AF) burden, activity level, lead parameters, and ventricular arrhythmia incidence and/or therapy., Results: Thirty-four patients with CA (7 with AL-CA, 27 with ATTR-CM [78% with wild-type]; 82% men) with median age of 75 years and a mean ejection fraction of 42 ± 13% had a CIED implanted for bradycardia (65%) or prevention of sudden cardiac death (35%). CIED implantation preceded CA diagnosis in 14 patients (41%). Over a mean follow-up of 3.1 ± 4.0 years, right ventricular sensing amplitudes decreased but did not result in device malfunction; lead impedances and capture thresholds remained stable. Between post-implantation years 1 and 5, mean ventricular pacing increased from 56 ± 9% to 96 ± 1% (p = 0.003) and AF burden increased from 2 ± 1.3 to 17 ± 3 h/day (p = 0.0002). Ventricular arrhythmias were common (mean episodes per patient per year: 6.7 ± 2.3 [ATTR-CM] and 5.1 ± 3.2 [AL-CA]) but predominately nonsustained; only 1 patient with AL-CA required implantable cardioverter-defibrillator therapy., Conclusions: Longitudinal analysis of CIED data in patients with CA revealed progressive conduction disease, with high AF burden and eventual dependence on ventricular pacing, although lead parameters remained stable. Ventricular arrhythmias were common but predominantly nonsustained, particularly in ATTR-CM., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Monogenic diseases are individually rare but collectively common, and are likely underdiagnosed., Objectives: The purpose of this study was to estimate the prevalence of monogenic cardiovascular diseases (MCVDs) and potentially missed diagnoses in a cardiovascular cohort., Methods: Exomes from 8,574 individuals referred for cardiac catheterization were analyzed. Pathogenic/likely pathogenic (P/LP) variants associated with MCVD (cardiomyopathies, arrhythmias, connective tissue disorders, and familial hypercholesterolemia were identified. Electronic health records (EHRs) were reviewed for individuals harboring P/LP variants who were predicted to develop disease (G+). G+ individuals who did not have a documented relevant diagnosis were classified into groups of whether they may represent missed diagnoses (unknown, unlikely, possible, probable, or definite) based on relevant diagnostic criteria/features for that disease., Results: In total, 159 P/LP variants were identified; 2,361 individuals harbored at least 1 P/LP variant, of whom 389 G+ individuals (4.5% of total cohort) were predicted to have at least 1 MCVD. EHR review of 342 G+ individuals predicted to have 1 MCVD with sufficient EHR data revealed that 52 had been given the relevant clinical diagnosis. The remaining 290 individuals were classified as potentially having an MCVD as follows: 193 unlikely (66.6%), 50 possible (17.2%), 30 probable (10.3%), and 17 definite (5.9%). Grouping possible, probable, definite, and known diagnoses, 149 were considered to have an MCVD. Novel MCVD pathogenic variants were identified in 16 individuals., Conclusions: Overall, 149 individuals (1.7% of cohort) had MCVDs, but only 35% were diagnosed. These patients represents a "missed opportunity," which could be addressed by greater use of genetic testing of patients seen by cardiologists., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Current exercise guidelines for clinical populations recommend an exercise therapy (ET) prescription of fixed intensity (moderate), duration (40-50 minutes per session), and volume (120-160 min/wk). A critical overarching element of exercise programming that has received minimal attention is dose scheduling. We investigated the tolerability and efficacy of 2 exercise training dose regimens on cardiorespiratory fitness and patient-reported outcomes in patients with posttreatment primary breast cancer., Methods: Using a parallel-group randomized trial, we randomly allocated 174 postmenopausal patients (2.8 years after adjuvant therapy) with impaired peak oxygen consumption (VO 2 peak) to 1 of 2 supervised exercise training interventions delivered with a standard linear (LET) (fixed dose intensity per session for 160 min/wk) or nonlinear (NLET) (variable dose intensity per session for ≈120 min/wk) schedule compared with a stretching attention control group for 16 consecutive weeks. Stretching was matched to exercise dosing arms on the basis of location, frequency, duration, and treatment length. The primary end point was change in VO 2 peak (mL O 2 ·kg -1 ·min -1 ) from baseline to after intervention. Secondary end points were patient-reported outcomes, tolerability, and safety., Results: No serious adverse events were observed. Mean attendance was 64%, 75%, and 80% for attention control, LET, and NLET, respectively. In intention-to-treat analysis, VO 2 peak increased 0.6±1.7 mL O 2 ·kg -1 ·min -1 ( P =0.05) and 0.8±1.8 mL O 2 ·kg -1 ·min -1 ( P =0.07) in LET and NLET, respectively, compared with attention control. Change in VO 2 peak ranged from -2.7 to 4.1 mL O 2 ·kg -1 ·min -1 and from -3.6 to 5.1 mL O 2 ·kg -1 ·min -1 in LET and NLET, respectively. Approximately 40% of patients in both exercise dosing regimens were classified as VO 2 peak responders (ie, Δ ≥1.32 mL O 2 ·kg -1 ·min -1 ). NLET improved all patient-reported outcomes compared with attention control., Conclusions: Short-term exercise training, independently of dosing schedule, is associated with modest improvements in cardiorespiratory fitness in patients previously treated for early-stage breast cancer., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01186367.

Transthyretin amyloid cardiomyopathy (ATTR-CM) has emerged as an increasingly identified etiology of heart failure. Fortunately, the disease now has an approved therapy, with many others under development. Assessment of prognosis in ATTR-CM is critical to inform patients about the disease course and guide clinical decisions. This review discusses the evidence behind clinical, biomarker, and imaging findings that inform prognosis in patients with ATTR-CM and can assist providers in the shared decision-making process during management of this disease., (© 2019 The Authors.)

Background: Circulating high-density lipoprotein particle (HDL-P) subfractions impact atherogenesis, inflammation, and endothelial function, all of which are implicated in the pathobiology of heart failure (HF)., Objectives: The authors sought to identify key differences in plasma HDL-P subfractions between patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) to determine their prognostic utility., Methods: Patients with HFrEF (n = 782), HFpEF (n = 1,004), and no HF (n = 4,742) were identified in the CATHGEN (Catheterization Genetics) biorepository of sequential patients undergoing cardiac catheterization. Nuclear magnetic resonance-based lipoprotein profiling was performed on frozen fasting plasma obtained at catheterization. The authors used multivariable analysis of covariance to compare high-density lipoprotein particle (HDL-P) subfractions across groups, and Cox proportional hazards modeling to determine associations between HDL-P subfractions and time to death or major adverse cardiac events., Results: Mean HDL-P size was greater in HFrEF than HFpEF, both of which were greater than in no HF (all 2-way p < 0.0001). By contrast, concentrations of small HDL-P and total HDL-P were lesser in HFrEF than HFpEF, which were both lesser than no HF (all 2-way p ≤ 0.0002). In both HFrEF and HFpEF, total HDL-P and small HDL-P were inversely associated with time to adverse events. These findings persisted after adjustment for 14 clinical covariates (including high-density lipoprotein cholesterol content, coronary artery disease, and the inflammatory biomarker GlycA), and in sensitivity analyses featuring alternate left ventricular ejection fraction definitions, or stricter inclusion criteria with diastolic dysfunction or left ventricular end-diastolic pressure thresholds., Conclusions: In the largest analysis of HDL-P subfractions in HF to date, derangements in HDL-P subfractions were identified that were more severe in HFrEF than HFpEF and were independently associated with adverse outcomes. These data may help refine risk assessment and provide new insights into the complex interaction of HDL and HF pathophysiology., (Copyright © 2019. Published by Elsevier Inc.)

Background: As the potential for cancer therapy-related cardiac dysfunction is increasingly recognized, there is a need for the standardization of echocardiographic measurements and cut points to guide treatment. The aim of this study was to determine the reproducibility of cardiac safety assessments across two academic echocardiography core laboratories (ECLs) at the University of Pennsylvania and the Duke Clinical Research Institute., Methods: To harmonize the application of guideline-recommended measurement conventions, the ECLs conducted multiple training sessions to align measurement practices for traditional and emerging assessments of left ventricular (LV) function. Subsequently, 25 echocardiograms taken from patients with breast cancer treated with doxorubicin with or without trastuzumab were independently analyzed by each laboratory. Agreement was determined by the proportion (coverage probability [CP]) of all pairwise comparisons between readers that were within a prespecified minimum acceptable difference. Persistent differences in measurement techniques between laboratories triggered retraining and reassessment of reproducibility., Results: There was robust reproducibility within each ECL but differences between ECLs on calculated LV ejection fraction and mitral inflow velocities (all CPs < 0.80); four-chamber global longitudinal strain bordered acceptable reproducibility (CP = 0.805). Calculated LV ejection fraction and four-chamber global longitudinal strain were sensitive to small but systematic interlaboratory differences in endocardial border definition that influenced measured LV volumes and the speckle-tracking region of interest, respectively. On repeat analyses, reproducibility for mitral velocities (CP = 0.940-0.990) was improved after incorporating multiple-beat measurements and homogeneous image selection. Reproducibility for four-chamber global longitudinal strain was unchanged after efforts to develop consensus between ECLs on endocardial border determinations were limited primarily by a lack of established reference standards., Conclusions: High-quality quantitative echocardiographic research is feasible but requires a commitment to reproducibility, adherence to guideline recommendations, and the time, care, and attention to detail to establish agreement on measurement conventions. These findings have important implications for research design and clinical care., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

1-Benzyl-indole-3-carbinol (1-benzyl-I3C), a synthetic analogue of the crucifer-derived natural phytochemical I3C, displayed significantly wider sensitivity and anti-proliferative potency in melanoma cells than the natural compound. Unlike I3C, which targets mainly oncogenic BRAF-expressing cells, 1-benzyl-I3C effectively inhibited proliferation of melanoma cells with a more extensive range of mutational profiles, including those expressing wild-type BRAF. In both cultured melanoma cell lines and in vivo in melanoma cell-derived tumor xenografts, 1-benzyl-I3C disrupted canonical Wnt/β-catenin signaling that resulted in the downregulation of β-catenin protein levels with a concomitant increase in levels of the β-catenin destruction complex components such as glycogen synthase kinase-3β (GSK-3β) and Axin. Concurrent with the inhibition of Wnt/β-catenin signaling, 1-benzyl-I3C strongly downregulated expression of the melanoma master regulator, microphthalmia-associated transcription factor isoform-M (MITF-M) by inhibiting promoter activity through the consensus lymphoid enhancer factor-1 (LEF-1)/T-cell transcription factor (TCF) DNA-binding site. Chromatin immunoprecipitation revealed that 1-benzyl-I3C downregulated interactions of endogenous LEF-1 with the MITF-M promoter. 1-Benzyl-I3C ablated Wnt-activated LEF-1-dependent reporter gene activity in a TOP FLASH assay that was rescued by expression of a constitutively active form of the Wnt co-receptor low-density lipoprotein receptor-related protein (LRP6), indicating that 1-benzyl-I3C disrupts Wnt/β-catenin signaling at or upstream of LRP6. In oncogenic BRAF-expressing melanoma cells, combinations of 1-benzyl-I3C and Vemurafenib, a clinically employed BRAF inhibitor, showed strong anti-proliferative effects. Taken together, our observations demonstrate that 1-benzyl-I3C represents a new and highly potent indolecarbinol-based small molecule inhibitor of Wnt/β-catenin signaling that has intriguing translational potential, alone or in combination with other anti-cancer agents, to treat human melanoma., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Cancer is associated with a prothrombotic state and increases the risk of thrombotic events in patients with atrial fibrillation. We described the clinical characteristics and outcomes and assessed the safety and efficacy of apixaban versus warfarin in patients with atrial fibrillation and cancer in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial., Methods: The association between cancer and clinical outcomes was assessed using Cox regression models. At baseline, 1236 patients (6.8%) had a history of cancer; 12.7% had active cancer, and 87.3% had remote cancer., Results: There were no significant associations between history of cancer and stroke/systemic embolism, major bleeding, or death. The effect of apixaban versus warfarin for the prevention of stroke/systemic embolism was consistent among patients with a history of cancer (event/100 patient-years = 1.4 vs 1.2; hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.53-2.26) and no cancer (1.3 vs 1.6; HR, 0.77; 95% CI, 0.64-0.93) (P interaction = .37). The safety and efficacy of apixaban versus warfarin were preserved among patients with and without active cancer. Apixaban was associated with a greater benefit for the composite of stroke/systemic embolism, myocardial infarction, and death in active cancer (HR, 0.30; 95% CI, 0.11-0.83) versus without cancer (HR, 0.86; 95% CI, 0.78-0.95), but not in remote cancer (HR, 1.46; 95% CI, 1.01-2.10) (interaction P = .0028)., Conclusions: Cancer was not associated with a higher risk of stroke. The superior efficacy and safety of apixaban versus warfarin were consistent in patients with and without cancer. Our positive findings regarding apixaban use in patients with atrial fibrillation and cancer are exploratory and promising, but warrant further evaluation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: While abnormal resting LV GLS has been described in patients with chronic heart failure with preserved ejection fraction (HFpEF), its prognostic significance when measured during an acute heart failure hospitalization remains unclear. We assessed the association between left ventricular global longitudinal strain (LV GLS) and outcomes in patients hospitalized with acute HFpEF., Methods and Results: We studied patients discharged alive for acute HFpEF from Duke University Medical Center between 2007 and 2010. Among patients with measurable LV GLS, we performed 2D, speckle-tracking analysis and Cox proportional hazards models assessed the association between continuous LV GLS and outcomes. Baseline characteristics were stratified by normal (≤-16%) or abnormal (>-16%) LV GLS for comparison. Among 463 patients, the median LV GLS was -12.8% (Interquartile range, -15.8 to -10.8%) and was abnormal in 352 (76%). Overall patients in the cohort were generally elderly, female and had hypertension. After multivariable adjustment, worse outcomes were noted between LV GLS and mortality (HR 1.19 per 1% increase; 95% CI 1.00-1.42; P = 0.046) and a composite endpoint of mortality or rehospitalization at 30 days (HR 1.08 per 1% increase; 95% CI 0.99-1.18; P = 0.08). There was no association between LV GLS and mortality or a composite of mortality or rehospitalization at 1 year., Conclusions: A high prevalence of patients hospitalized with acute HFpEF have abnormal LV GLS suggesting unrecognized myocardial systolic dysfunction. Furthermore, worse LV GLS is associated with worse clinical outcomes at 30 days but not by1 year., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Cardiac allografts are routinely evaluated by left ventricular ejection fraction (LVEF) before and after transplantation. However, myocardial deformation analyses with LV global longitudinal strain (GLS) are more sensitive for detecting impaired LV myocardial systolic performance compared with LVEF., Methods: We analyzed echocardiograms in 34 heart donor-recipient pairs transplanted at Duke University from 2000 to 2013. Assessments of allograft LV systolic function by LVEF and/or LV GLS were performed on echocardiograms obtained pre-explanation in donors and serially in corresponding recipients., Results: Donors had a median LVEF of 55% (25th, 75th percentile, 54% to 60%). Median donor LV GLS was -14.6% (-13.7 to -17.3%); LV GLS was abnormal (ie, >-16%) in 68% of donors. Post-transplantation, LV GLS was further impaired at 6 weeks (median -11.8%; -11.0 to -13.4%) and 3 months (median -11.4%; -10.3 to -13.9%) before recovering to pretransplant levels in follow-up. Median LVEF remained ≥50% throughout follow-up. We found no association between donor LV GLS and post-transplant outcomes, including all-cause hospitalization and mortality., Conclusions: GLS demonstrates allograft LV systolic dysfunction in donors and recipients not detected by LVEF. The clinical implications of subclinical allograft dysfunction detected by LV GLS require further study., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hematopoietic cell transplantation (HCT) has been used for curative intent in patients with hematologic and nonhematologic malignancies, resulting in an increasing number of HCT survivors. These survivors are at risk for serious and life-threatening complications, including cardiovascular disease (CVD). This article provides an overview of CVD in HCT survivors, describing the pathophysiology of disease, with a special emphasis on therapeutic exposures and comorbidities unique to this population. This article also discusses novel screening and prevention strategies that have shown promise in non-HCT cancer populations, emphasizing opportunities for collaboration between cardiologists and hematologists to improve the cardiovascular health of HCT survivors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The oral vasopressin-2 receptor antagonist tolvaptan causes aquaresis in patients with volume overload, potentially facilitating decongestion and improving the clinical course of patients with acute heart failure (AHF)., Objectives: The TACTICS-HF (Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure) study was conducted to address the acute use of tolvaptan to improve congestion in AHF., Methods: The TACTICS-HF study randomized patients (n = 257) within 24 h of AHF presentation in a prospective, double blind, placebo-controlled trial. Patients were eligible regardless of ejection fraction, and were randomized to either 30 mg of tolvaptan or placebo given at 0, 24, and 48 h, with a fixed-dose furosemide regimen as background therapy. The primary endpoint was the proportion of patients considered responders at 24 h. Secondary endpoints included symptom improvement, changes in renal function, and clinical events., Results: Dyspnea relief by Likert scale was similar between groups at 8 h (25% moderately or markedly improved with tolvaptan vs. 28% placebo; p = 0.59) and at 24 h (50% tolvaptan vs. 47% placebo; p = 0.80). Need for rescue therapy was also similar at 24 h (21% tolvaptan, 18% placebo; p = 0.57). The proportion defined as responders at 24 h (primary study endpoint) was 16% for tolvaptan and 20% for placebo (p = 0.32). Tolvaptan resulted in greater weight loss and net fluid loss compared with placebo, but tolvaptan-treated patients were more likely to experience worsening renal function during treatment. There were no differences in in-hospital or post-discharge clinical outcomes., Conclusions: In patients hospitalized with AHF, dyspnea, and congestion, the addition of tolvaptan to a standardized furosemide regimen did not improve the number of responders at 24 h, despite greater weight loss and fluid loss. (Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure [TACTICS-HF]; NCT01644331)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Indole-3-carbinol (I3C), an anti-cancer phytochemical derived from cruciferous vegetables, strongly inhibited proliferation and down-regulated protein levels of the melanocyte master regulator micropthalmia-associated transcription factor (MITF-M) in oncogenic BRAF-V600E expressing melanoma cells in culture as well as in vivo in tumor xenografted athymic nude mice. In contrast, wild type BRAF-expressing melanoma cells remained relatively insensitive to I3C anti-proliferative signaling. In BRAF-V600E-expressing melanoma cells, I3C treatment inhibited phosphorylation of MEK and ERK/MAPK, the down stream effectors of BRAF. The I3C anti-proliferative arrest was concomitant with the down-regulation of MITF-M transcripts and promoter activity, loss of endogenous BRN-2 binding to the MITF-M promoter, and was strongly attenuated by expression of exogenous MITF-M. Importantly, in vitro kinase assays using immunoprecipitated BRAF-V600E and wild type BRAF demonstrated that I3C selectively inhibited the enzymatic activity of the oncogenic BRAF-V600E but not of the wild type protein. In silico modeling predicted an I3C interaction site in the BRAF-V600E protomer distinct from where the clinically used BRAF-V600E inhibitor Vemurafenib binds to BRAF-V600E. Consistent with this prediction, combinations of I3C and Vemurafenib more potently inhibited melanoma cell proliferation and reduced MITF-M levels in BRAF-V600E expressing melanoma cells compared to the effects of each compound alone. Thus, our results demonstrate that oncogenic BRAF-V600E is a new cellular target of I3C that implicate this indolecarbinol compound as a potential candidate for novel single or combination therapies for melanoma. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF)., Methods and Results: We identified HFpEF cases, HFrEF controls, and no-HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No-HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long-chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no-HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance., Conclusions: We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Anthracycline-containing chemotherapy (Anth-C) is associated with long-term cardiovascular mortality. Although cardiovascular risk assessment has traditionally focused on the heart, evidence has demonstrated that vascular dysfunction also occurs during and up to 1 year following Anth-C. Whether vascular dysfunction persists long-term or negatively influences cardiac function remains unknown. Hence, the present study evaluated ventricular-arterial coupling, in concert with measures of vascular structure and function, in the years following Anth-C., Methods: Arterial elastance (Ea), end-systolic elastance (Ees), and ventricular-arterial coupling (Ea/Ees) were measured during rest and exercise using echocardiography. Resting vascular function (flow-mediated dilation) and structure (carotid intima-media thickness, arterial stiffness) were also measured., Results: Thirty breast cancer survivors (6.5 ± 3.6 years after Anth-C) with normal left ventricular ejection fraction (LVEF) (60% ± 6%) and 30 matched controls were studied. At rest, no differences were found in Ea, Ees, Ea/Ees, or LVEF between groups. The normal exercise-induced increase in Ees was attenuated in survivors at 50% and 75% of maximal workload (p < .01). Ea/Ees was also higher at all workloads in the survivors compared with the controls (p < .01). No differences in vascular structure and function were observed between the two groups (p > .05)., Conclusion: In the years after Anth-C, ventricular-arterial coupling was significantly attenuated during exercise, primarily owing to decreased LV contractility (indicated by a reduced Ees). This subclinical dysfunction appears to be isolated to the heart, as no differences in Ea were observed. The previously reported adverse effects of Anth-C on the vasculature appear to not persist in the years after treatment, as vascular structure and function were comparable to controls., Implications for Practice: Anthracycline-induced cardiotoxicity results in significantly impaired ventricular-arterial coupling in the years following chemotherapy, owing specifically to decreased left ventricular contractility. This subclinical dysfunction was identified only under exercise stress. A comprehensive evaluation of vascular structure and function yielded no differences between those treated with anthracyclines and controls. Combined with a stress stimulus, ventricular-arterial coupling might hold significant value beyond characterization of integrative cardiovascular function, in particular as a part of a risk-stratification strategy after anthracycline-containing chemotherapy. Although vascular function and structure were not different in this cohort, this does not undermine the importance of identifying vascular (dys)function in this population, because increases in net arterial load during exercise might amplify the effect of reductions in contractility on cardiovascular function after anthracycline-containing chemotherapy., (©AlphaMed Press.)

Objectives: This study was performed to determine whether a 4-tiered classification of left ventricular hypertrophy (LVH) defines subgroups in the general population that are at variable risks of adverse cardiovascular (CV) outcomes., Background: We recently proposed a 4-tiered classification of LVH where eccentric LVH is subdivided into "indeterminate hypertrophy" and "dilated hypertrophy" and concentric LVH into "thick hypertrophy" and "both thick and dilated hypertrophy," based on the presence of increased left ventricular (LV) end-diastolic volume., Methods: Participants from the Dallas Heart study who underwent cardiac magnetic resonance and did not have LV dysfunction or a history of heart failure (HF) (n = 2,458) were followed for a median of 9 years for the primary outcome of HF or CV death. Multivariable Cox proportional hazards models were used to adjust for age, sex, African-American race, hypertension, diabetes, and history of CV disease., Results: In the cohort, 70% had no LVH, 404 (16%) had indeterminate hypertrophy, 30 (1%) had dilated hypertrophy, 289 (12%) had thick hypertrophy, and 7 (0.2%) had both thick and dilated hypertrophy. The cumulative incidence of HF or CV death was 2% with no LVH, 1.7% with indeterminate, 16.7% with dilated, 11.1% with thick, and 42.9% with both thick and dilated hypertrophy (log-rank p < 0.0001). Compared with participants without LVH, those with dilated (hazard ratio [HR]: 7.3; 95% confidence interval [CI]: 2.8 to 18.8), thick (HR: 2.4; 95% CI: 1.4 to 4.0), and both thick and dilated (HR: 5.8; 95% CI: 1.7 to 19.5) hypertrophy remained at increased risk for HF or CV death after multivariable adjustment, whereas the group with indeterminate hypertrophy was not (HR: 0.9; 95% CI: 0.4 to 2.2)., Conclusions: In the general population, the 4-tiered classification system for LVH stratified LVH into subgroups with differential risk of adverse CV outcomes., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease and cancer increasingly coexist, yet relationships between cancer and long-term cardiovascular outcomes post-percutaneous coronary intervention (PCI) are not well studied., Methods and Results: We examined stented PCI patients at Duke (1996-2010) using linked data from the Duke Information Systems for Cardiovascular Care and the Duke Tumor Registry (a cancer treatment registry). Our primary outcome was cardiovascular mortality. Secondary outcomes included composite cardiovascular mortality, myocardial infarction, or repeat revascularization and all-cause mortality. We used adjusted cause-specific hazard models to examine outcomes among cancer patients (cancer treatment pre-PCI) versus controls (no cancer treatment pre-PCI). Cardiovascular mortality was explored in a cancer subgroup with recent (within 1 year pre-PCI) cancer and in post-PCI cancer patients using post-PCI cancer as a time-dependent variable. Among 15 008 patients, 3.3% (n=496) were cancer patients. Observed rates of 14-year cardiovascular mortality (31.4% versus 27.7%, P=0.31) and composite cardiovascular death, myocardial infarction, or revascularization (51.1% versus 55.8%, P=0.37) were similar for cancer versus control groups; all-cause mortality rates were higher (79.7% versus 49.3%, P<0.01). Adjusted risk of cardiovascular mortality was similar for cancer patients versus controls (hazard ratio 0.95; 95% CI 0.76 to 1.20) and for patients with versus without recent cancer (hazard ratio 1.46; 95% CI 0.92 to 2.33). Post-PCI cancer, present in 4.3% (n=647) of patients, was associated with cardiovascular mortality (adjusted hazard ratio 1.51; 95% CI 1.11 to 2.03)., Conclusions: Cancer history was present in a minority of PCI patients but was not associated with worse long-term cardiovascular outcomes. Further investigation into PCI outcomes in this population is warranted., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Advancements in diagnostic tools and curative-intent therapies have improved cancer-specific survival. With prolonged survival, patients are now subject to increased aging and development of cardiovascular risk factors such that further improvements in cancer-specific mortality are at risk of being offset by increased cardiovascular mortality. Moreover, established and novel adjuvant therapies used in cancer treatment are associated with unique and varying degrees of direct as well as indirect myocardial and cardiovascular injury (i.e., cardiotoxicity). Current approaches for evaluating anticancer therapy-induced injury have limitations, particularly lack of sensitivity for early detection of subclinical cardiac and cardiovascular dysfunction. With emerging evidence suggesting early prevention and treatment can mitigate the degree of cardiotoxicity and limit interruption of life-saving cancer therapy, the importance of early detection is increasingly paramount. Newer imaging modalities, functional capacity testing and blood biomarkers have the potential to improve early detection of cardiotoxicity and reduce cardiovascular morbidity and mortality.

Background: The purpose of this study was to investigate the extent of pre-exercise participation ("preparticipation") health screening in a heterogeneous cohort of adult cancer patients., Methods: Patients (n = 413) with histologically confirmed solid or hematologic malignancy were categorized into preparticipation health screening risk stratification based on American College Sports Medicine (ACSM) recommendations. Risk of an exercise-related event was evaluated during a symptom-limited cardiopulmonary exercise test (CPET) with 12-lead electrocardiography (ECG)., Results: Participant risk was categorized as low risk (n = 59, 14%), moderate risk (n = 217, 53%), and high risk (n = 137, 33%). Mean peak oxygen consumption was 21.7 ± 6.7 mL/kg(-1) per minute(-1) or 19.5 ± 21.7% below age- and sex-predicted sedentary values. No major serious adverse events or fatal events were observed during CPET procedures. A total of 31 positive ECG tests were observed, for an event rate of 8%. ACSM risk stratification did not predict the risk of a positive test. Age, statin use, antiplatelet therapy use, cardiovascular disease, prior treatment with anthracycline or radiation therapy, and being sedentary were predictors of a positive test (all p < .10)., Conclusion: The patient risk-stratification profile strongly suggests that the use of formalized preparticipation health screening is required in all oncology scenarios; however, risk of an exercise-induced event is low, suggesting that the use of exercise testing is not required for pre-exercise clearance in the majority of patients., (©AlphaMed Press.)

Purpose: To investigate the efficacy and safety of aerobic training (AT) in patients with cancer with medically stable heart failure (HF)., Patients and Methods: A retrospective analysis of 90 patients with cancer who have HF and who were randomly assigned to AT (n = 47) or guideline-based usual care (UC; n = 43) was performed. AT consisted of three supervised sessions per week at 20 to 45 minutes per session at 60% to 70% of heart rate reserve for 12 weeks followed by home-based sessions for 4 to 12 months. The primary end point was all-cause mortality and hospitalization. Secondary end points were other clinical events, safety, and change in exercise capacity (VO(2peak)) and health-related quality of life (HRQOL)., Results: Median follow-up was 35 months. In intention-to-treat (ITT) analyses, all-cause mortality or hospitalization at 2 years was 74% in the AT group compared with 67% in the UC group (adjusted hazard ratio [HR], 1.11; 95% CI, 0.69 to 1.77; P = .676). The incidence of cardiovascular mortality or cardiovascular hospitalization was significantly higher in the AT group compared with the UC group (41% v 67%; adjusted HR, 1.94; 95% CI, 1.12 to 3.16; P = .017). There were no differences in any VO(2peak) or HRQOL end points. In post hoc analyses based on adherence to AT, all-cause mortality and hospitalization was 66% in adherent patients (≥ 90 minutes per week) compared with 84% in nonadherent patients (< 90 minutes per week)., Conclusion: In ITT analyses, AT did not improve clinical outcomes in patients with cancer who had HF. Post hoc analyses suggested that patients not capable of adhering to the planned AT prescription may be at increased risk of clinical events., (© 2014 by American Society of Clinical Oncology.)

Unlabelled: Erectile dysfunction (ED) is a major adverse effect of radical prostatectomy (RP). We conducted a randomized controlled trial to examine the efficacy of aerobic training (AT) compared with usual care (UC) on ED prevalence in 50 men (n=25 per group) after RP. AT consisted of five walking sessions per week at 55-100% of peak oxygen uptake (VO2peak) for 30-60 min per session following a nonlinear prescription. The primary outcome was change in the prevalence of ED, as measured by the International Index of Erectile Function (IIEF), from baseline to 6 mo. Secondary outcomes were brachial artery flow-mediated dilation (FMD), VO2peak, cardiovascular (CV) risk profile (eg, lipid profile, body composition), and patient-reported outcomes (PROs). The prevalence of ED (IIEF score ≤ 21) decreased by 20% in the AT group and by 24% in the UC group (difference: p=0.406). There were no significant between-group differences in any erectile function subscale (p>0.05). Significant between-group differences were observed for changes in FMD and VO2peak, favoring AT. There were no group differences in other markers of CV risk profile or PROs. In summary, nonlinear AT does not improve ED in men with localized prostate cancer in the acute period following RP., Trial Registration: Clinicaltrials.gov identifier NCT00620932., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Conventional resting left ventricular ejection fraction (LVEF) assessments have limitations for detecting doxorubicin (DOX)-related cardiac dysfunction. Novel resting echocardiographic parameters, including 3-dimensional echocardiography (3DE) and global longitudinal strain (GLS), have potential for early identification of chemotherapy-related myocardial injury. Exercise "stress" is an established method to uncover impairments in cardiac function but has received limited attention in the adult oncology setting. We evaluated the utility of an integrated approach using 3DE, GLS, and exercise stress echocardiography for detecting subclinical cardiac dysfunction in early breast cancer patients treated with DOX-containing chemotherapy. Fifty-seven asymptomatic women with early breast cancer (mean 26 ± 22 months post-chemotherapy) and 20 sex-matched controls were studied. Resting left ventricular (LV) function was assessed by LVEF using 2-dimensional echocardiography (2DE) and 3DE and by GLS using 2-dimensional speckle-tracking echocardiography (2D-STE). After resting assessments, subjects completed cardiopulmonary exercise testing with stress 2DE. Resting LVEF was lower in patients than controls by 3DE (55 ± 4 vs. 59 ± 5 %; p = 0.005) but not 2DE (56 ± 4 vs. 58 ± 3 %; p = 0.169). 10 of 51 (20 %) patients had GLS greater than or equal to -17 %, which was below the calculated lower limit of normal (control mean 2SD); this patient subgroup had a mean 20 % impairment in GLS (-16.1 ± 0.9 vs. -20.1 ± 1.5 %; p < 0.001), despite similar LVEF by 2DE and 3DE compared to controls (p > 0.05). Cardiopulmonary function (VO2peak) was 20 % lower in patients than controls (p < 0.001). Exercise stress 2DE assessments of stroke volume (61 ± 11 vs. 69 ± 15 ml; p = 0.018) and cardiac index (2.3 ± 0.9 vs. 3.1 ± 0.8 l min(-1) m(-2) mean increase; p = 0.003) were lower in patients than controls. Post-exercise increase in cardiac index predicted VO2peak (r = 0.429, p = 0.001). Resting 3DE, GLS, and exercise stress 2DE detect subclinical cardiac dysfunction not apparent with resting 2DE in post-DOX breast cancer patients.

Aims: Pre-implant assessment of longitudinal mechanical dyssynchrony using cross-correlation analysis (XCA) was tested for association with long-term survival and compared with other tissue Doppler imaging (TDI)-derived indices., Methods and Results: In 131 patients referred for cardiac resynchronization therapy (CRT) from two international centres, mechanical dyssynchrony was assessed from TDI velocity curves using time-to-peak opposing wall delay (OWD) ≥80 ms, Yu index ≥32 ms, and the maximal activation delay (AD-max) >35 ms. AD-max was calculated by XCA of the TDI-derived myocardial acceleration curves. Outcome was a composite of all-cause mortality, cardiac transplantation, or implantation of a ventricular assist device (left ventricular assist device) and modelled using the Cox proportional hazards regression. Follow-up was truncated at 1460 days. Dyssynchrony by AD-max was independently associated with improved survival when adjusted for QRS > 150 ms and aetiology {hazard ratio (HR) 0.35 [95% confidence interval (CI) 0.16-0.77], P = 0.01}. Maximal activation delay performed significantly better than Yu index, OWD, and the presence of left bundle branch block (P < 0.05, all, for difference between parameters). In subgroup analysis, patients without dyssynchrony and QRS between 120 and 150 ms showed a particularly poor survival [HR 4.3 (95% CI 1.46-12.59), P < 0.01, compared with the group with dyssynchrony and QRS between 120 and 150 ms]., Conclusion: Mechanical dyssynchrony assessed by AD-max was associated with long-term survival after CRT and was significantly better associated compared with other TDI-derived indices. Patients without dyssynchrony and QRS between 120 and 150 ms had a particularly poor prognosis. These results indicate a valuable role for XCA in selection of CRT candidates.

Background: Evaluation of myocardial deformation by two-dimensional speckle-tracking is useful for clinical and research purposes. However, differences may exist among different ultrasound machines, software packages, frame rates, and observers., Methods: Thirty patients underwent echocardiography on both GE (Vivid 9; GE Vingmed Ultrasound AS, Horten, Norway) and Philips (iE33; Philips Ultrasound, Bothell, WA) ultrasound systems. From each study, two sets of images were stored in Digital Imaging and Communications in Medicine format, optimized for strain evaluation: one set of images at the acquisition frame rate (55-90 frames/sec) and one set of images at a compressed frame rate of 30 frames/sec. Vendor-independent software (VIS; TomTec 2D Cardiac Performance Analysis, Munich, Germany) was used to measure strain in multiple directions and was compared with vendor-specific software (GE EchoPAC; GE Vingmed Ultrasound AS)., Results: Intraobserver and interobserver coefficients of variation ranged from 5.5% to 8.7% for longitudinal strain, from 10.7% to 20.8% for circumferential, and from 15.3% to 33.4% for radial and transverse strain. Strain values obtained using VIS were comparable with those obtained using vendor-specific software for longitudinal strain, regardless of ultrasound machine or frame rate. For circumferential strain, a consistent large bias was observed between VIS and vendor-specific software, with higher values using VIS. Slightly higher strain values were observed by analysis at the acquisition frame rate compared with the low frame rate, but no consistent bias was observed between images from different vendors., Conclusions: Global longitudinal strain consistently showed good reproducibility, while reproducibility was moderate for circumferential strain and poor in the radial direction. Retrospective analysis of legacy Digital Imaging and Communications in Medicine data at 30 frames/sec can be reliably performed for longitudinal strain., (Copyright © 2012 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Background: Left ventricular hypertrophy (LVH) is traditionally classified as concentric or eccentric, based on the ratio of LV wall thickness to chamber dimension. We propose a 4-tiered LVH classification based on LV concentricity(0.67) (mass/end-diastolic volume(0.67)) and indexed LV end-diastolic volume (EDV)., Methods and Results: Cardiac MRI was performed in 2803 subjects and LVH (n=895) was defined by increased LV mass/height(2.7). Increased concentricity(0.67) and indexed EDV were defined at the 97.5th percentile of a healthy subpopulation. Four geometric patterns resulted: increased concentricity without increased EDV ("thick hypertrophy," n=361); increased EDV without increased concentricity ("dilated hypertrophy," n=53); increased concentricity with increased EDV ("both thick and dilated hypertrophy," n=13); and neither increased concentricity nor increased EDV ("indeterminate hypertrophy," n=468). Compared with subjects with isolated thick hypertrophy, those with both thick and dilated hypertrophy had a lower LV ejection fraction and higher NT-pro-BNP and BNP levels (P

To determine age-related changes in left ventricular (LV) structure and function, the authors used freehand three-dimensional echocardiography, a previously validated tomographic technique, to measure LV mass, volumes, and derived parameters in 94 sedentary, but ambulatory and clinically healthy, adult male and female volunteers aged 20-94. LV volumes and mass were significantly greater in men than in women (p<0.001) and remained greater after adjustment for body surface area and height (p<0.05). Declines in end-diastolic and stroke volumes with age were reduced or absent after accounting for body size. By multivariate analysis, age accounted for only about 6%-11% of the variance among LV volumes and mass, in comparison with body surface area and gender, which accounted jointly for about 46%-77% of the variance. In conclusion, changes occur in LV structure and function with normal aging, but these changes are relatively minor when body size and gender are taken into account.