Progression of Coronary Artery Calcium and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis.

BackgroundAlthough the association between coronary artery calcium (CAC) and future heart failure (HF) has been shown previously, the value of CAC progression in the prediction of HF has not been investigated. In this study, we investigated the association of CAC progression with subclinical left ventricular (LV) dysfunction and incident HF in the Multi-Ethnic Study of Atherosclerosis.Methods and resultsThe Multi-Ethnic Study of Atherosclerosis is a population-based study consisting of 6814 men and women aged 45 to 84, free of overt cardiovascular disease at enrollment, who were recruited from 4 ethnicities. We included 5644 Multi-Ethnic Study of Atherosclerosis participants who had baseline and follow-up cardiac computed tomography and were free of HF and coronary heart disease before the second cardiac computed tomography. Mean (±SD) age was 61.7±10.2 years and 47.2% were male. The Cox proportional hazard models and multivariable linear regression models were deployed to determine the association of CAC progression with incident HF and subclinical LV dysfunction, respectively. Over a median follow-up of 9.6 (interquartile range: 8.8-10.6) years, 182 participants developed incident HF. CAC progression of 10 units per year was associated with 3% of increased risk of HF independent of overt coronary heart disease (P=0.008). In 2818 participants with available cardiac magnetic resonance images, CAC progression was associated with increased LV end diastolic volume (β=0.16; P=0.03) and LV end systolic volume (β=0.12; P=0.006) after excluding participants with any coronary heart disease.ConclusionsCAC progression was associated with incident HF and modestly increased LV end diastolic volume and LV end systolic volume at follow-up exam independent of overt coronary heart disease

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\u27), while RV diastolic function was evaluated by early right ventricular tissue velocity (RVE\u27). 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 (beta=-0.082, SE=0.031, p=0.008), RVS\u27 (beta=-0.343, SE=0.156, p=0.028) and RVE\u27 (beta=-0.715, SE=0.195, p \u3c 0.001) compared with never smokers. Former smokers had a significantly lower RVE\u27 compared with never smokers (beta=-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

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 × 10 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

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

Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients

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

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

BackgroundOur understanding of the specific aspects of vascular contributions to dementia remains unclear.ObjectivesWe aim to identify the correlates of incident dementia in a multi-ethnic cardiovascular cohort.MethodsA 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.ResultsOver 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.ConclusionIn 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

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

Abstract 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