Growth/differentiation factor 15 (GDF15) expression in the heart after myocardial infarction and cardioprotective effect of pre-ischemic rGDF15 administration.

Growth/differentiation factor-15 (GDF15) is considered an unfavourable prognostic biomarker for cardiovascular disease in clinical data, while experimental studies suggest it has cardioprotective potential. This study focuses on the direct cardiac effects of GDF15 during ischemia-reperfusion injury in Wistar male rats, employing concentrations relevant to patients at high cardiovascular risk. Initially, we examined circulating levels and heart tissue expression of GDF15 in rats subjected to ischemia-reperfusion and sham operations in vivo. We then evaluated the cardiac effects of GDF15 both in vivo and ex vivo, administering recombinant GDF15 either before 30 min of ischemia (preconditioning) or at the onset of reperfusion (postconditioning). We compared infarct size and cardiac contractile recovery between control and rGDF15-treated rats. Contrary to our expectations, ischemia-reperfusion did not increase GDF15 plasma levels compared to sham-operated rats. However, cardiac protein and mRNA expression increased in the infarcted zone of the ischemic heart after 24 h of reperfusion. Notably, preconditioning with rGDF15 had a cardioprotective effect, reducing infarct size both in vivo (65 ± 5% in control vs. 42 ± 6% in rGDF15 groups) and ex vivo (60 ± 4% in control vs. 45 ± 4% in rGDF15 groups), while enhancing cardiac contractile recovery ex vivo. However, postconditioning with rGDF15 did not alter infarct size or the recovery of contractile parameters in vivo or ex vivo. These novel findings reveal that the short-term exogenous administration of rGDF15 before ischemia, at physiologically relevant levels, protects the heart against ischemia-reperfusion injury in both in vivo and ex vivo settings. The ex vivo results indicate that rGDF15 operates independently of the inflammatory, endocrine and nervous systems, suggesting direct and potent cardioprotective properties against ischemia-reperfusion injury.

Short-Term Postnatal Overfeeding Induces Long-Lasting Cardiometabolic Syndrome in Mature and Old Mice Associated with Increased Sensitivity to Myocardial Infarction.

SCOPE: Perinatal nutritional disturbances may "program" an increased cardio-metabolic risk in adulthood; however, few experimental studies have explored their effects on mature and/or old animal. This study aims to investigate the influence of postnatal overfeeding (PNOF) on cardiac function, sensitivity to ischemia-reperfusion (I-R) injury in vivo, glucose metabolism, and metabolic profile of pericardial adipose tissue (PAT) in young (4 months), adult (6 months), old (12 months), and very old (18 months) male mice. METHODS AND RESULTS: Two days after birth, PNOF is induced by adjusting the litter size of C57BL/6 male mice to three pups/mother, while the normally fed (NF) control group is normalized to nine pups/mother. After weaning, all mice have free access to standard diet. Glucose/insulin tests and in vivo myocardial I-R injury are conducted on mice aged from 2 to 12 months, while echocardiography is performed at all ages up to 18 months. PNOF mice exhibit an early and persistent 10-20% increase in body weight and a 10% decrease in left ventricular ejection fraction throughout their lifespan. In PNOF mice aged 4, 6, and 12 months, glucose intolerance and insulin resistance are observed, as well as a 27-34% increase in infarct size. This is accompanied by a higher PAT mass with increased inflammatory status. CONCLUSION: Short-term PNOF results in nutritional programming, inducing long-lasting alterations in glucose metabolism and cardiac vulnerability in male mice, lasting up to 12 months.

Protein tyrosine phosphatase 1B regulates miR-208b-argonaute 2 association and thyroid hormone responsiveness in cardiac hypertrophy.

Increased production of reactive oxygen species plays an essential role in the pathogenesis of several diseases, including cardiac hypertrophy. In our search to identify redox-sensitive targets that contribute to redox signaling, we found that protein tyrosine phosphatase 1B (PTP1B) was reversibly oxidized and inactivated in hearts undergoing hypertrophy. Cardiomyocyte-specific deletion of PTP1B in mice (PTP1B cKO mice) caused a hypertrophic phenotype that was exacerbated by pressure overload. Furthermore, we showed that argonaute 2 (AGO2), a key component of the RNA-induced silencing complex, was a substrate of PTP1B in cardiomyocytes and in the heart. Our results revealed that phosphorylation at Tyr393 and inactivation of AGO2 in PTP1B cKO mice prevented miR-208b-mediated repression of thyroid hormone receptor-associated protein 1 (THRAP1; also known as MED13) and contributed to thyroid hormone-mediated cardiac hypertrophy. In support of this conclusion, inhibiting the synthesis of triiodothyronine (T3) with propylthiouracil rescued pressure overload-induced hypertrophy and improved myocardial contractility and systolic function in PTP1B cKO mice. Together, our data illustrate that PTP1B activity is cardioprotective and that redox signaling is linked to thyroid hormone responsiveness and microRNA-mediated gene silencing in pathological hypertrophy.

Programming of Cardiovascular Dysfunction by Postnatal Overfeeding in Rodents.

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.

Relation between pulse oximetry plethysmographic waveform amplitude induced by passive leg raising and cardiac index in spontaneously breathing subjects.

INTRODUCTION: Previous studies suggested that variation of pulse oximetric plethysmographic (POP) waveform amplitude (Delta POP) could predict fluid responsiveness in mechanically ventilated patients. Our objective was to correlate the variations of Delta POP and the variations of cardiac index (CI) induced by passive leg raising (PLR) in spontaneously breathing volunteers. METHODS: We studied 26 spontaneously breathing volunteers using a pulse oximeter attached to the middle finger. We assessed hemodynamic variables, including Delta POP (%) (POP(max) - POP(min))/[(POP(max) + POP(min))/2] and CI determined by transthoracic echocardiography at baseline (eg, semirecumbent position), during PLR at 60 degrees, and back to baseline. RESULTS: Cardiac index significantly increased from 2.2 to 2.5 L/min x m(2) (P < .01) at 60 degrees PLR. Conversely, Delta POP significantly decreased from 22% to 15% (P < .01) at 60 degrees PLR. There was a weak correlation between CI and Delta POP variations at 60 degrees PLR (r = 0.40; P < .01). The area under curve of the receiver operating characteristic curve for Delta POP as a predictor of an increase of CI of 15% was not significant (0.67 +/- 0.10; P = .16). CONCLUSION: The variation of Delta POP induced by PLR is not an accurate predictor of increase in CI.

Stroke in elderly patients: management and prognosis in the ED.

PURPOSE: The aim of the study was to analyze the effect of age on management and prognosis of stroke. METHODS: A retrospective study was performed in consecutive patients admitted to an emergency department (ED) with a diagnosis of stroke. Comparison according to age (< 75 vs > or = 75 years old) was done, with a 1-year follow-up including autonomy and outcome. RESULTS: In older patients, brain magnetic resonance imaging (6% vs 27%, P < .001) and immediate referral to the stroke unit were less frequent (6% vs 28%, P < .001); median length of stay was longer (11 vs 8 days, P = .007); and in-hospital mortality tended to be higher (12% vs 6%, not significant). After discharge, 1-year mortality was higher (27% vs 14%, P = .004). In a multivariate analysis, severity of stroke, hemorrhagic stroke, and dementia were independent positive predictors of 1-year mortality, whereas age was not. CONCLUSION: Despite the fact that age was not an independent predictor when stroke severity was considered, our data suggest differences in the management of elderly compared with younger stroke patients admitted to the ED.

Assessment of early administration of abciximab in acute ST-segment elevation myocardial infarction in the emergency room.

OBJECTIVE: Abciximab, a platelet glycoprotein IIb/IIIa inhibitor, administered in conjunction with primary coronary stenting, improves the outcome of acute myocardial infarction, and the earlier it is administered, the greater the improvement. We sought to assess the feasibility of early administration of abciximab in the emergency room (ER) before primary coronary stenting and compare our results with those of a group of patients treated in the prehospital (ambulance) phase. METHODS: Data and outcome of patients with acute ST-segment elevation myocardial infarction who received abciximab (0.25 mg x kg(-1) then 0.125 mg x kg(-1) x h(-1)) in the ER before primary coronary stenting were compared with those of patients who received abciximab in the prehospital phase. RESULTS: Characteristics of the group treated in the ER did not differ significantly from those of patients treated before arrival at the hospital, except for prevalence of diabetes (22 versus 5%, p<0.05) and administration of analgesic to control chest pain (22 versus 65%, p<0.05). Nor did the median time between onset of pain and abciximab administration differ significantly different (120 versus 160 min, NS). In contrast, the median delay between the beginning of abciximab administration and insertion of the cardiac catheter was significantly shorter in the ER group (35 versus 55 min, p<0.05). There were no significant differences between groups in TIMI flow grade before or after revascularization, specific revascularization performed, or outcome. CONCLUSION: Our study provides some evidence that early administration of abciximab in the ER is safe, feasible, and justified by the delay required for coronary revascularization.