Lung Structure and Longitudinal Change in Cardiac Structure and Function: The MESA COPD Study.

BACKGROUND: Lung structure and cardiac structure and function are associated cross-sectionally. The classic literature suggests relationships of airways disease to cor pulmonale and emphysema to reduced cardiac output (CO) but longitudinal data are lacking. METHODS: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease (COPD) Study was a multi-center longitudinal COPD case-control study of participants 50-79 years with ≥10 pack-years smoking without clinical cardiovascular disease. Segmental airway wall area (WA) and percent emphysema were measured on computed tomography. Right and left ventricle (RV, LV) parameters were assessed on magnetic resonance imaging (MRI) in exams six years apart. Longitudinal and period cross-sectional associations were evaluated with mixed models adjusted for demographics, body size, and smoking. RESULTS: The 187 participants with repeated MRI were 67±7 years old; 42% had COPD; 22% currently smoked; and the race/ethnicity distribution was 54% white, 30% Black, 14% Hispanic, and 3% Asian. Greater WA at enrollment was associated with longitudinal increase in RV mass (3.5 g per 10mm2 WA, 95% CI: 1.1, 5.9). Greater percent emphysema was associated with stably lower LV end diastolic volume (-7.8 mL per 5% emphysema, 95% CI: -10.3, -3.0) and CO (-0.2 L·min-1 per 5% emphysema, 95% CI: -0.4, -0.1). CONCLUSION: Cardiac associations varied by lung structure over six years in this multi-ethnic study. Greater WA at enrollment was associated with longitudinal increases in RV mass; whereas greater percent emphysema was associated with stable decrements in LV filling and CO.

Deep phenotyping of dementia in a multi-ethnic cardiovascular cohort: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Our understanding of the specific aspects of vascular contributions to dementia remains unclear. OBJECTIVES: We aim to identify the correlates of incident dementia in a multi-ethnic cardiovascular cohort. METHODS: A total of 6806 participants with follow-up data for incident dementia were included. Probable dementia diagnoses were identified using hospitalization discharge diagnoses according to the International Classification of Diseases Codes (ICD). We used Random Forest analyses to identify the correlates of incident dementia and cognitive function from among 198 variables collected at the baseline MESA exam entailing demographic risk factors, medical history, anthropometry, lab biomarkers, electrocardiograms, cardiovascular magnetic resonance imaging, carotid ultrasonography, coronary artery calcium and liver fat content. Death and stroke were considered competing events. RESULTS: Over 14 years of follow-up, 326 dementia events were identified. Beyond age, the top correlates of dementia included coronary artery calcification, high sensitivity troponin, common carotid artery intima to media thickness, NT-proBNP, physical activity, pulse pressure, tumor necrosis factor-α, history of cancer, and liver to spleen attenuation ratio from computed tomography. Correlates of cognitive function included income and physical activity, body size, serum glucose, glomerular filtration rate, measures of carotid artery stiffness, alcohol use, and inflammation indexed as IL-2 and TNF soluble receptors and plasmin-antiplasmin complex. CONCLUSION: In a deeply phenotyped cardiovascular cohort we identified the key correlates of dementia beyond age as subclinical atherosclerosis and myocyte damage, vascular function, inflammation, physical activity, hepatic steatosis, and history of cancer.

MRI-Based Breast Cancer Classification and Localization by Multiparametric Feature Extraction and Combination Using Deep Learning.

BACKGROUND: Deep learning (DL) have been reported feasible in breast MRI. However, the effectiveness of DL method in mpMRI combinations for breast cancer detection has not been well investigated. PURPOSE: To implement a DL method for breast cancer classification and detection using feature extraction and combination from multiple sequences. STUDY TYPE: Retrospective. POPULATION: A total of 569 local cases as internal cohort (50.2 ± 11.2 years; 100% female), divided among training (218), validation (73) and testing (278); 125 cases from a public dataset as the external cohort (53.6 ± 11.5 years; 100% female). FIELD STRENGTH/SEQUENCE: T1-weighted imaging and dynamic contrast-enhanced MRI (DCE-MRI) with gradient echo sequences, T2-weighted imaging (T2WI) with spin-echo sequences, diffusion-weighted imaging with single-shot echo-planar sequence and at 1.5-T. ASSESSMENT: A convolutional neural network and long short-term memory cascaded network was implemented for lesion classification with histopathology as the ground truth for malignant and benign categories and contralateral breasts as healthy category in internal/external cohorts. BI-RADS categories were assessed by three independent radiologists as comparison, and class activation map was employed for lesion localization in internal cohort. The classification and localization performances were assessed with DCE-MRI and non-DCE sequences, respectively. STATISTICAL TESTS: Sensitivity, specificity, area under the curve (AUC), DeLong test, and Cohen's kappa for lesion classification. Sensitivity and mean squared error for localization. A P-value <0.05 was considered statistically significant. RESULTS: With the optimized mpMRI combinations, the lesion classification achieved an AUC = 0.98/0.91, sensitivity = 0.96/0.83 in the internal/external cohorts, respectively. Without DCE-MRI, the DL-based method was superior to radiologists' readings (AUC 0.96 vs. 0.90). The lesion localization achieved sensitivities of 0.97/0.93 with DCE-MRI/T2WI alone, respectively. DATA CONCLUSION: The DL method achieved high accuracy for lesion detection in the internal/external cohorts. The classification performance with a contrast agent-free combination is comparable to DCE-MRI alone and the radiologists' reading in AUC and sensitivity. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Higher diet quality relates to better cardiac function in cancer survivors: The multi-ethnic study of atherosclerosis.

BACKGROUND: Cancer therapies induce cardiac injury and increase cardiovascular disease (CVD) risk. In non-cancer populations, higher diet quality is associated with protection against CVD, but the relationship between diet and cardiac function in cancer survivors is unknown. METHODS: This cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort included 113 cancer survivors (55 breast, 53 prostate, three lung, and three blood) and 4233 non-cancer controls. Dietary intake was reported via validated food frequency questionnaire. Alternate healthy eating index (AHEI) was calculated as a measure of quality. Cardiac function, determined as left ventricular ejection fraction (LVEF), was assessed by cardiac magnetic resonance. RESULTS: Cancer survivors had a lower LVEF compared to controls (61.3 ± 6.5% v 62.4 ± 6.1%, p = 0.04). In all participants, total fat (ß ± SE: -0.04 ± 0.01, p = 0.004), saturated fat (-0.11 ± 0.03, p < 0.001), and trans-fat (-0.36 ± 0.12, p = 0.002) intake were inversely associated with LVEF while AHEI (0.03 ± 0.01, p < 0.001) was positively associated with LVEF. Among cancer survivors only, sucrose intake was negatively related to LVEF (-0.15 ± 0.06, p = 0.02), and the ratio of unsaturated fat to saturated fat (2.7 ± 1.1, p = 0.01) and fiber intake (0.42 ± 0.14, p = 0.003) were positively related to LVEF. DISCUSSION: In cancer survivors, improved dietary fat and carbohydrate quality (i.e., greater consumption of unsaturated fatty acids and fiber) was associated with favorable cardiac function, while higher sucrose was associated with worse cardiac function. Further research is needed to confirm these findings and test whether changes in the identified dietary factors will modulate cardiac function in cancer survivors.

Oxidative Stress and Cardiovascular Risk Factors: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Introduction-Oxidative stress is linked to cardiovascular diseases (CVD) and is suggested to vary by sex. However, few population-level studies have explored these associations and the majority comprise populations with advanced CVD. We assessed urinary isoprostane concentrations, a standard measure of oxidative stress, in a relatively young and healthy cohort, hypothesizing that higher oxidative stress is associated with an adverse cardiometabolic profile and female sex. Methods-Oxidative stress was measured in 475 women and 266 men, aged 48-55 years, from the Coronary Artery Risk Development in Young Adults (CARDIA) study using urinary 8-isoprostane (IsoP) and 2,3-dinor-8-isoprostane (IsoP-M). Multivariable-adjusted regression was used to evaluate cross-sectional associations. As secondary analysis, previously measured plasma F2-isoprostanes (plasma IsoP) from another CARDIA subset was similarly analyzed. Results-Mean (SD) ages for men and women were 52.1(2.3) and 52.2(2.2) years, respectively (p = 0.46), and 39% of the participants self-identified as Black (vs. White). Before adjustments, female sex was associated with higher median urinary IsoP (880 vs. 704 ng/g creatinine in men; p < 0.01) and IsoP m (1675 vs. 1284 ng/g creatinine in men; p < 0.01). Higher body mass index (BMI), high-density cholesterol (HDL-C), and triglycerides, current smoking, and less physical activity were associated with higher oxidative stress. Diabetes was not associated with urinary IsoP but was associated with lower IsoP m and plasma IsoP. Higher serum creatinine showed diverging associations with higher plasma and lower urinary isoprostane concentrations. Conclusions-Different isoprostane entities exhibit varying association patterns with CVD risk factors, and therefore are complementary, rather than interchangeable, in assessment of oxidative stress. Still, consistently higher isoprostanes among women, smokers, less active persons, and those with higher BMI and plasma triglycerides could reflect higher oxidative stress among these groups. While urinary isoprostanes are indexed to urinary creatinine due to variations in concentration, caution should be exercised when comparing groups with differing serum creatinine.

The Additive Value of Radiomics Features Extracted from Baseline MR Images to the Barcelona Clinic Liver Cancer (BCLC) Staging System in Predicting Transplant-Free Survival in Patients with Hepatocellular Carcinoma: A Single-Center Retrospective Analysis.

BACKGROUND: To study the additive value of radiomics features to the BCLC staging system in clustering HCC patients. METHODS: A total of 266 patients with HCC were included in this retrospective study. All patients had undergone baseline MR imaging, and 95 radiomics features were extracted from 3D segmentations representative of lesions on the venous phase and apparent diffusion coefficient maps. A random forest algorithm was utilized to extract the most relevant features to transplant-free survival. The selected features were used alongside BCLC staging to construct Kaplan-Meier curves. RESULTS: Out of 95 extracted features, the three most relevant features were incorporated into random forest classifiers. The Integrated Brier score of the prediction error curve was 0.135, 0.072, and 0.048 for the BCLC, radiomics, and combined models, respectively. The mean area under the receiver operating curve (ROC curve) over time for the three models was 81.1%, 77.3%, and 56.2% for the combined radiomics and BCLC models, respectively. CONCLUSIONS: Radiomics features outperformed the BCLC staging system in determining prognosis in HCC patients. The addition of a radiomics classifier increased the classification capability of the BCLC model. Texture analysis features could be considered as possible biomarkers in predicting transplant-free survival in HCC patients.

Resistin and risks of incident heart failure subtypes and cardiac fibrosis: the Multi-Ethnic Study of Atherosclerosis.

AIMS: Resistin is a circulating inflammatory biomarker that is associated with cardiovascular disease. We investigated the associations of resistin and incident heart failure (HF) and its subtypes, as well as specific measures of subclinical HF (myocardial fibrosis and relevant biomarkers). METHODS: We analysed data from 1968 participants in the Multi-Ethnic Study of Atherosclerosis with measurements of plasma resistin levels at clinic visits from 2002 to 2005. Participants were subsequently followed for a median of 10.5 years for HF events. The associations between resistin levels and incident HF, HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF) were examined using multivariable Cox proportional hazards models. Linear regression models assessed the associations between resistin levels and myocardial fibrosis from cardiac magnetic resonance imaging, as well as hs-cTnT and NT-proBNP. RESULTS: The mean age of the cohort was 64.7 years, and 50.0% were female. Seventy-four participants (4%) developed incident HF during follow-up. In a Cox proportional hazards model adjusted for age, gender, education level, race/ethnicity, and traditional risk factors, higher resistin levels were significantly associated with incident HF (HR 1.44, CI 1.18-1.75, P = 0.001) and HFrEF (HR 1.47, CI 1.07-2.02, P = 0.016), but not with HFpEF (HR 1.25, CI 0.89-1.75, P = 0.195). Resistin levels showed no significant associations with myocardial fibrosis, NT-proBNP, or hs-cTnT levels. CONCLUSIONS: In a multi-ethnic cohort free of cardiovascular disease at baseline, elevated resistin levels were associated with incident HF, more prominently with incident HFrEF than HFpEF, but not with subclinical myocardial fibrosis or biomarkers of HF.

Oxidative Stress and Menopausal Status: The Coronary Artery Risk Development in Young Adults Cohort Study.

Background: Low endogenous estrogen concentrations after menopause may contribute to higher oxidative stress and greater cardiovascular disease (CVD) risk. However, differences in oxidative stress between similarly aged premenopausal and postmenopausal women are not well-characterized on a population level. We hypothesized that urinary isoprostane concentrations, a standard measure of systemic oxidative stress, are higher in women who have undergone menopause compared to premenopausal women. Methods and Results: We examined differences in urinary 8-isoprostane (iPF2α-III) and 2,3-dinor-8-isoprostane (iPF2α-III-M) indexed to urinary creatinine between 279 postmenopausal and 196 premenopausal women in the Coronary Artery Risk Development in Young Adults (CARDIA) study, using linear regression with progressive adjustment for sociodemographic factors and traditional CVD risk factors. Unadjusted iPF2α-III-M concentrations were higher among postmenopausal compared to premenopausal women (Median [25th, 75th percentile]: 1762 [1178, 2974] vs. 1535 [1067, 2462] ng/g creatinine; p = 0.01). Menopause was associated with 25.5% higher iPF2α-III-M (95% confidence interval [6.5-47.9]) adjusted for age, race, college education, and field center. Further adjustments for tobacco use (21.2% [2.9-42.6]) and then CVD risk factors (18.8% [0.1-39.6]) led to additional partial attenuation. Menopause was associated with higher iPF2α-III in Black but not White women. Conclusions: We conclude that postmenopausal women had higher oxidative stress, which may contribute to greater CVD risk. ClinicalTrials.gov Identifier: NCT00005130.

Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial.

BACKGROUND: Most cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility. METHODS: In this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups. RESULTS: In total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (-0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of -0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04). CONCLUSIONS: In patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI. TRIAL REGISTRATION NUMBER: NCT01458405.

Association of Pro-B-Type Natriuretic Peptide With Cardiac Magnetic Resonance-Measured Global and Regional Cardiac Function and Structure Over 10 Years: The MESA Study.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is widely used to diagnose and manage patients with heart failure. We aimed to investigate associations between NT-proBNP levels and development of global and regional myocardial impairment, dyssynchrony, and risk of developing myocardial scar over time. Methods and Results We included 2416 adults (45-84 years) without baseline clinical cardiovascular disease from MESA (Multi-Ethnic Study of Atherosclerosis). NT-proBNP was assessed at baseline (2000-2002). Cardiac magnetic resonance-measured left ventricular parameters were assessed at baseline and year 10 (2010-2012). Tagged cardiac magnetic resonance and myocardial dyssynchrony were assessed. We used linear and logistic regression models to study the relationships between quartiles of NT-proBNP levels and outcome variables. Left ventricular parameters decreased over time. After 10-year follow-up and adjusting for cardiovascular disease risk factors, people in the highest quartile had significantly greater decline in left ventricular ejection fraction (-1.60%; 95% CI, -2.26 to -0.94; P<0.01) and smaller decline in left ventricular end systolic volume index (-0.47 mL/m2; 95% CI, -1.18 to 0.23; P<0.01) compared with those in the lowest quartile. Individuals in the highest quartile had more severe risk factor adjusted global, mid, and apical regional dyssynchrony compared with those in the lowest, second, and third quartiles (all P-trend<0.05). Compared with the lowest-quartile group, the adjusted odds ratios for having myocardial scar was 1.3 (95% CI, 0.7-2.2) for quartile 2; 1.2 (95% CI, 0.6-2.3) for quartile 3; and 2.7 (95% CI, 1.4-5.5) for quartile 4 (P-trend=0.012) for the total sample. Conclusions Among participants without baseline clinical cardiovascular disease, higher baseline NT-proBNP concentration was significantly associated with subclinical changes in developing myocardial dysfunction, more severe cardiac dyssynchrony, and higher odds of having myocardial scar over a 10-year period independent of traditional cardiovascular disease risk factors.

A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial.

AIMS: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

Integrating baseline MR imaging biomarkers into BCLC and CLIP improves overall survival prediction of patients with hepatocellular carcinoma (HCC).

OBJECTIVES: We aimed to evaluate the independent predictive role of baseline imaging biomarkers for overall survival (OS) and transplant-free survival (TFS) in patients with HCC and assess the incremental value of these biomarkers to current staging systems. METHODS: In this retrospective IRB approved study, the clinical, laboratory, and imaging parameters of 304 HCC patients were collected. Cox regression model was utilized to identify the potential predictors of survival. Recursive partitioning test was utilized to identify the optimal ADC cutoff for stratifying patients' OS. Patients were stratified based on Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program (CLIP). Binary ADC value (above vs. below the cutoff) and tumor margin (well- vs. ill-defined) were integrated into BCLC and CLIP. OS and TFS was compared for patients based on standard criteria with and without imaging biomarkers. RESULTS: At baseline, patients with low tumor ADC and well-defined tumor margin (favorable imaging biomarkers) had longer survival, as compared to those with high ADC and ill-defined tumor margin (unfavorable imaging biomarkers) (median OS of 43 months vs. 7 months, respectively) (p < 0.001). Tumor ADC and tumor margin remained strong independent predictors of survival after adjustment for demographics, BCLC and CLIP staging, and tumor burden. Incorporating ADC and tumor margin improved performance of OS prediction by 9% in BCLC group and 6% in CLIP group. CONCLUSION: Incorporating ADC and tumor margin to current staging systems for HCC significantly improve prediction of OS and TFS of these criteria. KEY POINTS: • ADC and tumor margin are predictors of overall survival in HCC patients, independent of clinical, laboratory, and other imaging variables. • Adding ADC and tumor margin improved the prognostic value of BCLC and CLIP criteria by 9% and 6%, respectively. • High ADC and ill-defined tumor margin at baseline predicted poor survival, regardless of patient's liver function and general health status.

Association of smoking and right ventricular function in middle age: CARDIA study.

Objective: To evaluate the association of cigarette smoking and right ventricular (RV) systolic and diastolic functions in a population-based cohort of individuals at middle age. Methods: This cross-sectional study included participants who answered the smoking questionnaire and underwent echocardiography at the Coronary Artery Risk Development in Young Adulthood year 25 examination. RV systolic function was assessed by echocardiographic-derived tricuspid annular plane systolic excursion (TAPSE) and by right ventricular peak systolic velocity (RVS'), while RV diastolic function was evaluated by early right ventricular tissue velocity (RVE'). Multivariable linear regression models assessed the relationship of smoking with RV function, adjusting for age, sex, race, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, diabetes mellitus, alcohol consumption, pulmonary function, left ventricular systolic and diastolic function and coronary artery calcium score. Results: A total of 3424 participants were included. The mean age was 50±4 years; 57% were female; and 53% were black. There were 2106 (61%) never smokers, 750 (22%) former smokers and 589 (17%) current smokers. In the multivariable analysis, current smokers had significantly lower TAPSE (ß=-0.082, SE=0.031, p=0.008), RVS' (ß=-0.343, SE=0.156, p=0.028) and RVE' (ß=-0.715, SE=0.195, p<0.001) compared with never smokers. Former smokers had a significantly lower RVE' compared with never smokers (ß=-0.414, SE=0.162, p=0.011), whereas no significant difference in RV systolic function was found between former smokers and never smokers. Conclusions: In a large multicenter community-based biracial cohort of middle-aged individuals, smoking was independently related to both worse RV systolic and diastolic functions.

Association of soluble interleukin-2 receptor α and tumour necrosis factor receptor 1 with heart failure: The Multi-Ethnic Study of Atherosclerosis.

AIMS: Soluble tumour necrosis factor-α receptor 1 (sTNF-αR1) and interleukin-2 receptor α (sIL-2Rα) predict incident heart failure (HF) in the elderly population. However, the association of these biomarkers with HF in a multi-ethnic asymptomatic population is unclear. We aimed to investigate the association of sTNF-αR1 and sIL-2Rα with incident HF in a multi-ethnic population of middle age and older participants. METHODS AND RESULTS: The multi-ethnic study of atherosclerosis is a prospective population-based study of 6814 participants aged 45-84 years who were free of clinical cardiovascular disease at enrolment. We included 2869 participants with available sTNF-αR1 or sIL-2Rα level measurement at baseline multi-ethnic study of atherosclerosis exam (2000-2002). We used Cox proportional-hazards model to investigate the association between sTNF-αR1 and sIL-2Rα with incident HF after adjusting for traditional cardiovascular risk factors and coronary artery calcium score measured by cardiac computed tomography. Among the included participants, the mean (standard deviation) age was 61.6 (10.2) years and 46.7% were men. The median (interquartile range) sTNF-αR1 and sIL-2Rα were 1293 (1107-1547) and 901 (727-1154) pg/mL. During a median follow-up of 14.2 (interquartile range: 11.7-14.8) years, 130 participants developed HF. In multivariable analysis, the hazard ratio (95% confidence interval, P value) of incident HF for each standard deviation increment of log-transformed sTNF-αR1 and sIL-2Rα was 1.43 (1.21-1.7, P ≤ 0.001) and 1.26 (1.04-1.53, P = 0.02), respectively. Excluding participants with interim coronary heart disease, we found a statistically significant association between sTNF-αR1 and HF with hazard ratio of 1.39 (95% confidence interval: 1.11 to 1.74, P = 0.005) and sIL-2Rα and HF showing a hazard ratio of 1.39 (95% confidence interval: 1.09 to 1.76, P = 0.007). CONCLUSIONS: sTNF-αR1 and sIL-2Rα are associated with a higher risk of incident HF in a multi-ethnic cohort without a previous history of cardiovascular disease.

Temporal Changes in Resting Heart Rate, Left Ventricular Dysfunction, Heart Failure and Cardiovascular Disease: CARDIA Study.

BACKGROUND: The prognostic significance of temporal changes in resting heart rate in young adults for premature heart failure and cardiovascular disease is unclear. We investigated the association between temporal changes in resting heart rate in young adults and early adult risk factors, subsequent cardiac function, and the risk of heart failure and cardiovascular by middle age. METHODS: We examined 4343 Coronary Artery Risk Development in Young Adults (CARDIA) study participants (mean [SD] age was 29.9 [3.6] years at the CARDIA Year-5 examination [1990-1991], 49% of participants were men, and 45% were African-American). Adjusted linear regression models were used to assess the association between temporal changes in resting heart rate, early life cardiovascular disease risk factors, and midlife cardiac function. Cox proportional hazard regression models were used to relate temporal changes in resting heart rate to heart failure and cardiovascular disease. Outcomes were followed up until August 31, 2017. RESULTS: Higher alcohol consumption (ß = 0.03, P <0.001), lower physical activity (ß = 0.002, P = 001), smoking (ß = 1.58, P <0.001), men (P <0.001), African Americans (P <0.001), impaired left ventricular relaxation (e´,ß = -0.13, P = 0.002), and worse diastolic function (E/e´, ß = 0.1, P = 0.01) were associated with longitudinal increases in resting heart rate. We observed 268 cardiovascular disease and 74 heart failure events over a median of 26 years. In Cox models, baseline and temporal changes in resting heart rate were associated with higher risk of heart failure (hazard ratio [HR] =1.37 95% confidence interval [CI] [1.05-1.79] and HR = 1.38 95% CI [1.02-1.86]) and a higher risk cardiovascular disease (HR = 1.23 95% CI [1.07-1.42] and HR = 1.23 95% CI [1.05-1.44]). CONCLUSIONS: Baseline and temporal changes in resting heart rate in young adults were associated with incident heart failure and cardiovascular disease by midlife. Contributory factors were associations between temporal increases in resting heart rate and early adult risk factors and subsequent cardiac dysfunction.

Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial.

BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment. OBJECTIVES: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC. METHODS: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 108 allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers. RESULTS: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group. CONCLUSIONS: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC.

Reproducibility and Changes in Vena Caval Blood Flow by Using 4D Flow MRI in Pulmonary Emphysema and Chronic Obstructive Pulmonary Disease (COPD): The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Substudy.

BackgroundChronic obstructive pulmonary disease (COPD) is associated with hemodynamic changes in the pulmonary vasculature. However, cardiac effects are not fully understood and vary by phenotype of chronic lower respiratory disease.PurposeTo use four-dimensional (4D) flow MRI for comprehensive assessment of the right-sided cardiovascular system, assess its interrater and intraobserver reproducibility, and examine associations with venous return to the right heart in individuals with chronic COPD and emphysema.Materials and MethodsThe Multi-Ethnic Study of Atherosclerosis COPD substudy prospectively recruited participants who smoked and who had COPD and nested control participants from population-based samples. Electrocardiography and respiratory gated 4D flow 1.5-T MRI was performed at three sites with full volumetric coverage of the thoracic vessels in 2014-2017 with postbronchodilator spirometry and inspiratory chest CT to quantify percent emphysema. Net flow, peak velocity, retrograde flow, and retrograde fraction were measured on 14 analysis planes. Interrater reproducibility was assessed by two independent observers, and the principle of conservation of mass was employed to evaluate the internal consistency of flow measures. Partial correlation coefficients were adjusted for age, sex, race/ethnicity, height, weight, and smoking status.ResultsAmong 70 participants (29 participants with COPD [mean age, 73.5 years ± 8.1 {standard deviation}; 20 men] and 41 control participants [mean age, 71.0 years ± 6.1; 22 men]), the interrater reproducibility of the 4D flow MRI measures was good to excellent (intraclass correlation coefficient range, 0.73-0.98), as was the internal consistency. There were no statistically significant differences in venous flow parameters according to COPD severity (P > .05). Greater percent emphysema at CT was associated with greater regurgitant flow in the superior and inferior caval veins and tricuspid valve (adjusted r = 0.28-0.55; all P < .01), particularly in the superior vena cava.ConclusionFour-dimensional flow MRI had good-to-excellent observer variability and flow consistency. Percent emphysema at CT was associated with statistically significant differences in retrograde flow, greatest in the superior vena cava.© RSNA, 2019Online supplemental material is available for this article.See also the editorial by Choe in this issue.

Prevalence of Unexplained Left Ventricular Hypertrophy by Cardiac Magnetic Resonance Imaging in MESA.

Background Hypertrophic cardiomyopathy is defined as unexplained left ventricular ( LV ) hypertrophy (wall thickness ≥15 mm) and is prevalent in 0.2% of adults (1:500) in population-based studies using echocardiography. Cardiac magnetic resonance imaging ( MRI ) allows for more accurate wall thickness measurement across the entire ventricle than echocardiography. The prevalence of unexplained LV hypertrophy by cardiac MRI is unknown. MESA (Multi-Ethnic Study of Atherosclerosis) recruited individuals without overt cardiovascular disease 45 to 84 years of age. Methods and Results We studied 4972 individuals who underwent measurement of regional LV wall thickness by cardiac MRI as part of the MESA baseline exam. American Heart Association criteria were used to define LV segments. We excluded participants with hypertension, LV dilation (≥95% predicted end-diastolic volume) or dysfunction (ejection fraction ≤50%), moderate-to-severe left-sided valve lesions by cardiac MRI , severe aortic valve calcification by cardiac computed tomography (aortic valve Agatston calcium score >1200 in women or >2000 in men), obesity (body mass index >35 kg/m2), diabetes mellitus, and current smoking. Sixty-seven participants (aged 64±10 years, 9% female) had unexplained LV hypertrophy (wall thickness ≥15 mm in at least 2 adjacent LV segments), representing 1.4% (1 in 74) participants, 2.6% of men and 0.2% of women. Prevalence was similar across categories of race/ethnicity. Hypertrophy was focal in 17 (25.4%), intermediate in 44 (65.7%), and diffuse in 5 (7.5%) participants. Conclusions The prevalence of unexplained LV hypertrophy in a population-based cohort using cardiac MRI was 1.4%. This may have implications for the diagnosis of patients with hypertrophic cardiomyopathy and will require further study.

Cardiac and skeletal muscle effects in the randomized HOPE-Duchenne trial.

OBJECTIVE: To assess the feasibility, safety, and efficacy of intracoronary allogeneic cardiosphere-derived cells (CAP-1002) in patients with Duchenne muscular dystrophy (DMD). METHODS: The Halt Cardiomyopathy Progression (HOPE)-Duchenne trial is a phase I/II, randomized, controlled, open-label trial (NCT02485938). Patients with DMD >12 years old, with substantial myocardial fibrosis, were randomized (1:1) to usual care (control) or global intracoronary infusion of CAP-1002 (75 million cells). Participants were enrolled at 3 US medical centers between January and August 2016 and followed for 12 months. An independent Data and Safety Monitoring Board provided safety oversight. Cardiac function and structure were assessed by MRI, and analyzed by a blinded core laboratory. Skeletal muscle function was assessed by performance of the upper limb (PUL). RESULTS: Twenty-five eligible patients (mean age 17.8 years; 68% wheelchair-dependent) were randomized to CAP-1002 (n = 13) or control (n = 12). Incidence of treatment-emergent adverse events was similar between groups. Compared to baseline, MRI at 12 months revealed significant scar size reduction and improvement in inferior wall systolic thickening in CAP-1002 but not control patients. Mid-distal PUL improved at 12 months in 8 of 9 lower functioning CAP-1002 patients, and no controls (p = 0.007). CONCLUSIONS: Intracoronary CAP-1002 in DMD appears safe and demonstrates signals of efficacy on both cardiac and upper limb function for up to 12 months. Thus, future clinical research on CAP-1002 treatment of DMD cardiac and skeletal myopathies is warranted. CLASSIFICATION OF EVIDENCE: This phase I/II study provides Class II evidence that for patients with DMD, intracoronary CAP-1002 is feasible and appears safe and potentially effective.