Highlights • Anthracyclines and trastuzumab are effective chemotherapies that can cause cardiotoxicity. • Cardiotoxicity is due to a combination of ‘on-target’ and ‘off-target’ effects. • ...Neuregulin-1 in the microvascular endothelium is involved in cardiotoxicity. • ErbB2 could be a potential target for anticancer therapy. • Heme oxygenase-1 inhibition may be a strategy to enhance the response to chemotherapy. • Notch-1 is a novel target in trastuzumab-resistant breast cancer.
Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this ...meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer.
We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab.
Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I(2) = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I(2) = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I(2) = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis.
Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab.
In patients treated with cardiotoxic chemotherapies, the presence of cardiovascular risk factors and previous cardiac disease have been strongly correlated to the onset of cardiotoxicity. The ...influence of overweight and obesity as risk factors in the development of treatment-related cardiotoxicity in breast cancer (BC) was recently suggested. However, due to meta-analysis design, it was not possible to take into account associated cardiac risk factors or other classic risk factors for anthracycline (antineoplastic antibiotic) and trastuzumab (monoclonal antibody) cardiotoxicity.
Using prospective data collected from 2012-2014 in the French national multicenter prospective CANTO (CANcer TOxicities) study of 26 French cancer centers, we aimed to examine the association of body mass index (BMI) and cardiotoxicity (defined as a reduction in left ventricular ejection fraction LVEF > 10 percentage points from baseline to LVEF < 50%). In total, 929 patients with stage I-III BC (mean age 52 ± 11 years, mean BMI 25.6 ± 5.1 kg/m2, 42% with 1 or more cardiovascular risk factors) treated with anthracycline (86% epirubicin, 7% doxorubicin) and/or trastuzumab (36%), with LVEF measurement at baseline and at least 1 assessment post-chemotherapy were eligible in this interim analysis. We analyzed associations between BMI and cardiotoxicity using multivariate logistic regression. At baseline, nearly 50% of the study population was overweight or obese. During a mean follow-up of 22 ± 2 months following treatment completion, cardiotoxicity occurred in 29 patients (3.2%). The obese group was more prone to cardiotoxicity than the normal-weight group (9/171 versus 8/466; p = 0.01). In multivariate analysis, obesity (odds ratio OR 3.02; 95% CI 1.10-8.25; p = 0.03) and administration of trastuzumab (OR 12.12; 95% CI 3.6-40.4; p < 0.001) were independently associated with cardiotoxicity. Selection bias and relatively short follow-up are potential limitations of this national multicenter observational cohort.
In BC patients, obesity appears to be associated with an important increase in risk-related cardiotoxicity (CANTO, ClinicalTrials.gov registry ID: NCT01993498).
ClinicalTrials.gov NCT01993498.
We investigated incidence, risk factors for new-onset atrial fibrillation (NAF), and prognostic impact during septic shock in medical Intensive Care Unit (ICU) patients.
Prospective, observational ...study in a university hospital. Consecutive patients from 03/2011 to 05/2013 with septic shock were eligible. Exclusion criteria were age <18 years, history of AF, transfer with prior septic shock. Included patients were equipped with long-duration (7 days) Holter ECG monitoring. NAF was defined as an AF episode lasting >30 seconds. Patient characteristics, infection criteria, cardiovascular parameters, severity of illness, support therapies were recorded.
Among 66 patients, 29(44%) developed NAF; 10 (34%) would not have been diagnosed without Holter ECG monitoring. NAF patients were older, with more markers of heart failure (troponin and NT-pro-BNP), lower left ventricular ejection fraction (LVEF), longer QRS duration and more nonsustained supra ventricular arrhythmias (<30s) on day 1 than patients who maintained sinus rhythm. By multivariate analysis, age (OR: 1.06; p = 0.01) and LVEF<45% (OR: 13.01, p = 0.03) were associated with NAF. NAF did not predict 28 or 90 day mortality.
NAF is common, especially in older patients, and is associated with low ejection fraction. We did not find NAF to be independently associated with higher mortality.
To identify patterns summarizing the retinal vascular network in the elderly and to investigate the relationship of these vascular patterns with cardiovascular history.
We conducted a ...population-based study, the Montrachet study (Maculopathy Optic Nerve nuTRition neurovAsCular and HEarT diseases), in participants older than 75 years. The history of cardiovascular disease and a score-based estimation of their 10-year risk of cardiovascular mortality (Heart SCORE) were collected. Retinal vascular network analysis was performed by means of Singapore "I" Vessel Assessment (SIVA) software. Principal component analysis was used to condense the information contained in the high number of variables provided and to identify independent retinal vascular patterns.
Overall, 1069 photographs (1069 participants) were reviewed with SIVA software. The mean age was 80.0 ± 3.8 years. We extracted three vascular patterns summarizing 41.3% of the vascular information. The most clinically relevant pattern, Sparse vascular network, accounted for 17.4% of the total variance. It corresponded to a lower density in the vascular network and higher variability in vessel width. Diabetic participants with hypoglycemic treatment had a sparser vascular network pattern than subjects without such treatment (odds ratio, OR, 1.68; 95% CI, 1.04-2.72; P = 0.04). Participants with no history of cardiovascular disease who had a sparser vascular network were associated with a higher Heart SCORE (OR, 1.76; 95% CI, 1.08-2.25; P = 0.02).
Three vascular patterns were identified. The Sparse vascular network pattern was associated with having a higher risk profile for cardiovascular mortality risk at 10 years.
Growth differentiation factor-15 (GDF-15) has been identified as a strong marker of cardiovascular disease; however, no data are available concerning the role of GDF-15 in the occurrence of organ ...dysfunction during coronary artery bypass grafting (CABG) associated with cardiopulmonary bypass (CPB).
Five arterial blood samples were taken sequentially in 34 patients from anesthesia induction (IND) until 24 h after arrival at the intensive care unit (ICU). Plasma levels of GDF-15, follistatin-like 1 (FLST1), myeloperoxidases (MPO), hydroperoxides and plasma antioxidant status (PAS) were measured at each time-point. Markers of cardiac (cardiac-troponin I, cTnI) and renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL) and other classical biological factors and clinical data were measured.
Plasma GDF-15 levels increased gradually during and after surgery, reaching nearly three times the IND levels in the ICU (3,075±284 ng/L vs. 1,061±90 ng/L, p<0.001). Plasma MPO levels increased dramatically during surgery, attaining their highest level after unclamping (UNCLAMP) (49±11 ng/mL vs. 1,679±153 ng/mL, p<0.001) while PAS significantly decreased between IND and UNCLAMP (p<0.05), confirming the high oxidative status induced by this surgical procedure. ICU levels of GDF-15 correlated positively with cTnI and NGAL (p = 0.006 and p = 0.036, respectively), and also with hemoglobin and estimated glomerular filtration rate (eGFR). Among all the post-operative biomarkers available, only eGFR, NGAL and GDF-15 measured at ICU arrival were significantly associated with the onset of acute kidney injury (AKI). Patients with a EuroSCORE >3 were shown to have higher GDF-15 levels.
During cardiac surgery associated with CPB, GDF-15 levels increased substantially and were associated with markers of cardiac injury and renal dysfunction.
Contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) is frequent and associated with long-term renal impairment and ...mortality. Early markers of CIN are needed to improve risk stratification. We aimed to assess whether N-terminal fragment of pro B-type natriuretic peptide (Nt-proBNP) could be associated with CIN. From the French regional RICO survey, all the consecutive patients who underwent primary PCI for STEMI, from January 1, 2001, to December 3, 2013, were included. Nt-proBNP circulating levels were assessed on admission. CIN was defined as an increase in serum creatinine >26.5 μmol/L or >50% within 48 to 72 hours after PCI (KDIGO criteria). Of the 1,243 patients included, CIN occurred in 130 patients (10.4%). Nt-proBNP levels were 5 times greater in patients who developed CIN than without CIN (1,275 435 to 4,022 vs 247 79 to 986 pg/mL, p <0.001). Hospital mortality rate was markedly higher in patients with CIN (6.9% vs 1.1%, p <0.001). Nt-proBNP levels were univariate predictors for CIN as were age, hypertension, diabetes, smoking, previous stroke, heart rate, impaired left ventricular ejection fraction C-reactive protein, history of renal failure, anemia, and estimated glomerular filtration rate <30 ml/min/1.73 m2 at baseline. Nt-proBNP levels remained strongly associated with the occurrence of CIN even after adjustment for risk factors, treatments, clinical and biological variables (odds ratio 1.99, 95% confidence interval 1.49 to 2.66). Net reclassification improvement was achieved by the addition of Nt-proBNP to the risk model (p = 0.003). In conclusion, from this large contemporary prospective study in nonselected population, our work suggests that Nt-proBNP levels at admission could help to identify patients at risk of CIN beyond traditional risk factors.
Nutritional environment in the perinatal period has a great influence on health and diseases in adulthood. In rodents, litter size reduction reproduces the effects of postnatal overnutrition in ...infants and reveals that postnatal overfeeding (PNOF) not only permanently increases body weight but also affects the cardiovascular function in the short- and long-term. In addition to increased adiposity, the metabolic status of PNOF rodents is altered, with increased plasma insulin and leptin levels, associated with resistance to these hormones, changed profiles and levels of circulating lipids. PNOF animals present elevated arterial blood pressure with altered vascular responsiveness to vasoactive substances. The hearts of overfed rodents exhibit hypertrophy and elevated collagen content. PNOF also induces a disturbance of cardiac mitochondrial respiration and produces an imbalance between oxidants and antioxidants. A modification of the expression of crucial genes and epigenetic alterations is reported in hearts of PNOF animals. In vivo, a decreased ventricular contractile function is observed during adulthood in PNOF hearts. All these alterations ultimately lead to an increased sensitivity to cardiac pathologic challenges such as ischemia-reperfusion injury. Nevertheless, caloric restriction and physical exercise were shown to improve PNOF-induced cardiac dysfunction and metabolic abnormalities, drawing a path to the potential therapeutic correction of early nutritional programming.
Abstract Background Pre-operative GDF-15 plasma levels significantly improve the prognostic value of the EuroSCORE for mortality after cardiac surgery. However, despite the strong correlation between ...GDF-15 and renal function, no data are available regarding the potential interest of pre-operative GDF-15 levels to improve the prediction of acute kidney injury (AKI) after cardiac artery bypass graft (CABG) surgery. Methods All patients operated on by 2 surgeons for CABG surgery at our university hospital from September 2011 to March 2013 were screened for participation in this prospective, observational study. Exclusion criteria: age < 18 years or > 80 years, previous atrial fibrillation/flutter, previous severe renal failure, previous cardiac surgery, emergency surgery. AKI was defined according to KDIGO criteria. GDF-15 levels in plasma were measured before induction and 12 h after surgery. Results 134 patients were included in this study. 42 (31%) developed post-operative AKI. AKI patients had a significantly higher pre-operative log-GDF-15 level (OR = 3.64; 95% CI = 1.41–9.40, p = 0.008), a lower pre-operative eGFR (OR = 0.98; 95% CI = 0.96–0.99; p = 0.026), and most often underwent on-pump surgery (OR = 2.60; 95% CI = 1.14–5.96, p = 0.024). On ROC curves, GDF-15 before induction was found to be the best pre-operative biomarker to predict AKI (AUC = 0.83; CI = 0.75–0.89), compared with eGFR (AUC = 0.67; 95% CI = 0.59–0.75), p = 0.003 and NT-proBNP (AUC = 0.62; CI = 0.51–0.72), p < 0.001. Pre-operative GDF-15 was also significantly better than the EuroSCORE in predicting AKI (AUC 0.62, 95% CI = 0.54–0.70), p < 0.001. Conclusions Pre-operative GDF-15 plasma levels are associated with post-operative AKI in CABG patients. If confirmed in larger cohorts, pre-operative GDF-15 may be of value to improve pre-operative risk stratification among candidates for surgery.
Iodinated contrast agent (ICA)-induced acute kidney injury (AKI) following acute coronary syndrome (ACS) is a frequent complication, which may lead to chronic kidney disease and increased mortality. ...Optical coherence tomography angiography (OCT-A) of the retina is new tool delivering a rapid and noninvasive assessment of systemic microvascularization, which is potentially involved in the occurrence of ICA-induced AKI. Between October 2016 and March 2017, 452 ACS patients were admitted to our cardiac intensive care unit. OCT-A was performed within 48 h after the ICA injection. Patients with a history of retinal disease were excluded. The patients included were divided into two groups depending on whether or not AKI occurred after injection of ICA, according to KDIGO criteria. Of the 216 patients included, 21 (10%) presented AKI. AKI was significantly associated with age, Mehran score, GRACE score, and NT-proBNP. AKI patients had significantly lower retinal vascular density (RVD)) and had more frequent low RVD (81% vs 45%, P = 0.002). Adding low RVD to the Mehran score and the NT-proBNP, or to the GRACE score and the NT-proBNP, significantly improved their predictive values, suggesting that systemic microvascular involvement remains incompletely addressed by either standard risk scores or factors known to be associated with ICA-induced AKI.
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