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BACKGROUND - Cardiac injury, as measured by troponin elevation, has been reported among hospitalized coronavirus disease 2019 (COVID-19) patients and portends a poor prognosis. However, how the dynamics of troponin elevation interplay with inflammation and coagulation biomarkers over time is unknown. We assessed longitudinal follow-up of cardiac injury, inflammation and coagulation markers in relation to disease severity and outcome.
METHODS - We retrospectively assessed 2068 patients with laboratory-confirmed COVID-19 between January 29 and April 1, 2020 at Tongji Hospital in Wuhan, China. We defined cardiac injury as an increase in high sensitivity cardiac troponin-I (hs-cTnI) above the 99th of the upper reference limit. We explored the dynamics of elevation in hs-cTnI and the relationship with inflammation (interleukin [IL]-6, IL-8, IL-10, IL-2 receptor, tumor necrosis factor-α, C-reactive protein) and coagulation (d-dimer, fibrinogen, international normalized ratio) markers in non-critically ill versus critically ill patients longitudinally and further correlated these markers to survivors and non-survivors.
RESULTS - Median age was 63 years (first to third quartile 51-70 years), 51.4% of whom were women. When compared to non-critically ill patients (N = 1592, 77.0%), critically ill (defined as requiring mechanical ventilation, in shock or multiorgan failure) patients (N = 476, 23.0%), had more frequent cardiac injury on admission (30.3% vs. 2.3%, p < 0.001), with increased mortality during hospitalization (38.4% vs. 0%, p < 0.001). Among critically ill patients, non-survivors (N = 183) had a continuous increase in hs-cTnI levels during hospitalization, while survivors (N = 293) showed a decrease in hs-cTnI level between day 4 and 7 after admission. Specifically, cardiac injury is an independent marker of mortality among critically ill patients at admission, day 4-7 and 8-14. Consistent positive correlations between hs-cTnI and interleukin (IL)-6 on admission (r = 0.59), day 4-7 (r = 0.66) and day 8-14 (r = 0.61; all p < 0.001) and d-dimer (at the same timepoints r = 0.54; 0.65; 0.61, all p < 0.001) were observed. A similar behavior was observed between hs-cTnI and most of other biomarkers of inflammation and coagulation.
CONCLUSIONS - Cardiac injury commonly occurs in critically ill COVID-19 patients, with increased levels of hs-cTnI beyond day 3 since admission portending a poor prognosis. A consistent positive correlation of hs-cTnI with IL-6 and d-dimer at several timepoints along hospitalization could suggest nonspecific cytokine-mediated cardiotoxicity.
Copyright © 2020. Published by Elsevier Ltd.
PURPOSE - Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs.
PATIENTS AND METHODS - Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs.
RESULTS - Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib ( = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; < .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank = .01) and overall survival (log-rank < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications.
CONCLUSION - CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.
BACKGROUND - Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized.
OBJECTIVES - The authors sought to understand the presentation and clinical course of ICI-associated myocarditis.
METHODS - After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block.
RESULTS - The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates.
CONCLUSIONS - Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.
Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Pulmonary hypertension (PH), remains a challenging disease with a large impact on both humans and meat-type chickens. PH is characterized by the onset of idiopathic pulmonary arterial hypertension leading to right ventricular failure. In this experiment relative gene expression of adenosine A receptor (ADORA1), serotonin transporter (SERT), phosphodiesterase 5A (PDE5) and troponin T2 were compared in hearts from broilers with acute right ventricular failure and from healthy birds. There were major increases in adenosine A receptor (177%) and serotonin transporter (475%), and more modest but significant increases in PDE5 (146%) and troponin T2 (140%) gene expressions in broilers with right ventricular failure compared to healthy birds (P<0.01). This novel report shows that pulmonary hypertension related gene expression in broilers is similar to that in humans. This molecular similarity between PH in broilers and human patients suggests, first, that they will make a suitable animal model for study PH in humans, but also that the literature on PH in humans may be profitably applied to the study of PH in broilers.
Copyright © 2017. Published by Elsevier Ltd.
Primary dilated cardiomyopathy (DCM) is a non-ischemic heart disease with impaired pumping function of the heart. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a healthy volunteer and a primary DCM patient to investigate the impact of DCM on iPSC-CMs׳ responses to different types of anisotropic strain. A bioreactor system was established that generates cardiac-mimetic forces of 150 kPa at 5% anisotropic cyclic strain and 1 Hz frequency. After confirming cardiac induction of the iPSCs, it was determined that fibronectin was favorable to other extracellular matrix protein coatings (gelatin, laminin, vitronectin) in terms of viable cell area and density, and was therefore selected as the coating for further study. When iPSC-CMs were exposed to three strain conditions (no strain, 5% static strain, and 5% cyclic strain), the static strain elicited significant induction of sarcomere components in comparison to other strain conditions. However, this induction occurred only in iPSC-CMs from a healthy volunteer ("control iPSC-CMs"), not in iPSC-CMs from the DCM patient ("DCM iPSC-CMs"). The donor type also significantly influenced gene expressions of cell-cell and cell-matrix interaction markers in response to the strain conditions. Gene expression of connexin-43 (cell-cell interaction) had a higher fold change in healthy versus diseased iPSC-CMs under static and cyclic strain, as opposed to integrins α-5 and α-10 (cell-matrix interaction). In summary, our iPSC-CM-based study to model the effects of different strain conditions suggests that intrinsic, genetic-based differences in the cardiomyocyte responses to strain may influence disease manifestation in vivo.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) hold great promise for modeling human heart diseases. However, iPSC-CMs studied to date resemble immature embryonic myocytes and therefore do not adequately recapitulate native adult cardiomyocyte phenotypes. Since extracellular matrix plays an essential role in heart development and maturation in vivo, we sought to develop a synthetic culture matrix that could enhance functional maturation of iPSC-CMs in vitro. In this study, we employed a library of combinatorial polymers comprising of three functional subunits - poly-ε-caprolacton (PCL), polyethylene glycol (PEG), and carboxylated PCL (cPCL) - as synthetic substrates for culturing human iPSC-CMs. Of these, iPSC-CMs cultured on 4%PEG-96%PCL (each % indicates the corresponding molar ratio) exhibit the greatest contractility and mitochondrial function. These functional enhancements are associated with increased expression of cardiac myosin light chain-2v, cardiac troponin I and integrin alpha-7. Importantly, iPSC-CMs cultured on 4%PEG-96%PCL demonstrate troponin I (TnI) isoform switch from the fetal slow skeletal TnI (ssTnI) to the postnatal cardiac TnI (cTnI), the first report of such transition in vitro. Finally, culturing iPSC-CMs on 4%PEG-96%PCL also significantly increased expression of genes encoding intermediate filaments known to transduce integrin-mediated mechanical signals to the myofilaments. In summary, our study demonstrates that synthetic culture matrices engineered from combinatorial polymers can be utilized to promote in vitro maturation of human iPSC-CMs through the engagement of critical matrix-integrin interactions.
Published by Elsevier Ltd.
OBJECTIVES - This analysis aimed to perform a head-to-head comparison of 3 of the promising biomarkers of cardiovascular (CV) outcomes in heart failure (HF)-soluble ST2 (sST2), growth differentiation factor (GDF)-15, and highly-sensitive troponin T (hsTnT)-and to evaluate the role of serial measurement of these biomarkers in patients with chronic HF.
BACKGROUND - sST2, GDF-15, and hsTnT are strongly associated with CV outcomes in HF.
METHODS - This post-hoc analysis used data from a study in which 151 patients with chronic HF due to left ventricular systolic dysfunction were followed up over 10 months. At each visit, N-terminal pro-B-type natriuretic peptide (NT-proBNP), sST2, GDF-15, and hsTnT were measured and any major CV events were recorded.
RESULTS - Baseline values of all 3 novel biomarkers independently predicted total CV events even after adjusting for clinical and biochemical characteristics, including NT-proBNP, with the best model including all 3 biomarkers (p < 0.001). Adding serial measurement to the base model appeared to improve the model's predictive ability (with sST2 showing the most promise), but it is not clear whether this addition is a unique contribution. However, when time-dependent factors were included, only sST2 serial measurement independently added to the risk model (odds ratio: 3.64; 95% confidence interval: 1.37 to 9.67; p = 0.009) and predicted reverse myocardial remodeling (odds ratio: 1.22; 95% confidence interval: 1.04 to 1.43; p = 0.01).
CONCLUSIONS - In patients with chronic HF, baseline measurement of novel biomarkers added independent prognostic information to clinical variables and NT-proBNP. Only serial measurement of sST2 appeared to add prognostic information to baseline concentrations and predicted change in left ventricular function. (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting (PROTECT)]; NCT00351390).
Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Currently available screening tools for left ventricular (LV) hypertrophy (LVH) and systolic dysfunction (LVSD) are either expensive (echocardiography) or perform suboptimally (B-type natriuretic peptide [BNP]). It is unknown whether newer biomarkers are associated with LVH and LVSD and can serve as screening tools.
METHODS AND RESULTS - We studied 2460 Framingham Study participants (mean age 58 years, 57% women) with measurements of biomarkers mirroring cardiac biomechanical stress (soluble ST-2 [ST2], growth differentiation factor-15 [GDF-15] and high-sensitivity troponin I [hsTnI]) and BNP. We defined LVH as LV mass/height(2) ≥the sex-specific 80th percentile and LVSD as mild/greater impairment of LV ejection fraction (LVEF) or a fractional shortening <0.29. Adjusting for standard risk factors in logistic models, BNP, GDF-15, and hsTnI were associated with the composite echocardiographic outcome (LVH or LVSD), odds ratios (OR) per SD increment in log-biomarker 1.29, 1.14, and 1.18 (95% CI: 1.15 to 1.44, 1.004 to 1.28, and 1.06 to 1.31), respectively. The C-statistic for the composite outcome increased from 0.765 with risk factors to 0.770 adding BNP, to 0.774 adding novel biomarkers. The continuous Net Reclassification Improvement was 0.212 (95% CI: 0.119 to 0.305, P<0.0001) after adding the novel biomarkers to risk factors plus BNP. BNP was associated with LVH and LVSD in multivariable models, whereas GDF-15 was associated with LVSD (OR 1.41, 95% CI: 1.16 to 1.70), and hsTnI with LVH (OR 1.22, 95% CI: 1.09 to 1.36). ST2 was not significantly associated with any outcome.
CONCLUSIONS - Our community-based investigation suggests that cardiac stress biomarkers are associated with LVH and LVSD but may have limited clinical utility as screening tools.
BACKGROUND - Growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) are emerging predictors of adverse clinical outcomes. We examined whether circulating concentrations are related to the development of kidney disease in the community.
METHODS - Plasma GDF-15, sST2, and hsTnI concentrations were measured in 2614 Framingham Offspring cohort participants (mean age 57 years, 54% women) at the sixth examination cycle (1995-1998). Associations of biomarkers with incident chronic kidney disease [CKD, eGFR <60 mL · min(-1) · (1.73 m(2)) (-1), n = 276], microalbuminuria (urinary albumin to creatinine ratio ≥25 mg/g in women and 17 mg/g in men, n = 191), and rapid decline in renal function [decline in eGFR ≥3 mL · min(-1) · (1.73 m(2)) (-1) per year, n = 237], were evaluated using multivariable logistic regression; P < 0.006 was considered statistically significant in primary analyses.
RESULTS - Participants were followed over a mean of 9.5 years. Higher plasma GDF-15 was associated with incident CKD [multivariable-adjusted odds ratio (OR) 1.9 per 1-U increase in log-GDF-15, 95% CI 1.6-2.3, P < 0.0001] and rapid decline in renal function (OR, 1.6; 95% CI, 1.3-1.8; P < 0.0001). GDF-15, sST2, and hsTnI had suggestive associations with incident microalbuminuria but did not meet the prespecified P-value threshold after multivariable adjustment. Adding plasma GDF-15 to clinical covariates improved risk prediction of incident CKD: the c-statistic increased from 0.826 to 0.845 (P = 0.0007), and categorical net reclassification was 6.3% (95% CI, 2.7-9.9%).
CONCLUSIONS - Higher circulating GDF-15 is associated with incident renal outcomes and improves risk prediction of incident CKD. These findings may provide insights into the mechanisms of renal injury.