Intralipid protects the heart in late pregnancy against ischemia/reperfusion injury via Caveolin2/STAT3/GSK-3ß pathway.

BACKGROUND: We recently demonstrated that the heart of late pregnant (LP) rodents is more prone to ischemia/reperfusion (I/R) injury compared to non-pregnant rodents. Lipids, particularly polyunsaturated fatty acids, have received special attention in the field of cardiovascular research. Here, we explored whether Intralipid (ITLD) protects the heart against I/R injury in LP rodents and investigated the mechanisms underlying this protection. METHODS AND RESULTS: In-vivo female LP rat hearts or ex-vivo isolated Langendorff-perfused LP mouse hearts were subjected to ischemia followed by reperfusion with PBS or ITLD (one bolus of 5mg/kg of 20% in in-vivo and 1% in ex-vivo). Myocardial infarct size, mitochondrial calcium retention capacity, genome-wide expression profiling, pharmacological inhibition and co-immunoprecipitation were performed. One bolus of ITLD at reperfusion significantly reduced the in-vivo myocardial infarct size in LP rats (23.3±2% vs. 55.5±3.4% in CTRL, p<0.01). Postischemic administration of ITLD also protected the LP hearts against I/R injury ex-vivo. ITLD significantly increased the threshold for the opening of the mitochondrial permeability transition pore in response to calcium overload (nmol-calcium/mg-mitochondrial protein: 290±17 vs. 167±10 in CTRL, p<0.01) and significantly increased phosphorylation of STAT3 (1.8±0.08 vs. 1±0.16 in CTRL, p<0.05) and GSK-3ß (2.63±0.55 vs. 1±0.0.34 in CTRL, p<0.05). The ITLD-induced cardioprotection was fully abolished by Stattic, a specific inhibitor of STAT3. Transcriptome analysis revealed caveolin 2 (Cav2) was significantly upregulated by ITLD in hearts of LP rats under I/R injury. Co-immunoprecipitation experiments showed that Cav2 interacts with STAT3. CONCLUSIONS: ITLD protects the heart in late pregnancy against I/R injury by inhibiting the mPTP opening through Cav2/STAT3/GSK-3ß pathway.

Baseline severity but not gender modulates quantified Crataegus extract effects in early heart failure--a pooled analysis of clinical trials.

OBJECTIVE: The efficacy of quantified Crataegus extract in chronic heart failure (CHF) has been assessed in numerous clinical studies. The present pooled analysis evaluates the impact of baseline severity and gender on objective and patient-reported endpoints and associations between both types of outcomes in patients with early CHF. METHODS: Available data from 687 individual patients treated with quantified Crataegus extract or placebo in ten studies were pooled. Treatment effects on physiologic outcome parameters and on symptoms were analysed for their association with baseline severity and gender. Changes in symptom scores were investigated with respect to their relation to physiologic outcome parameters. Results were compared with observations in a 3-year cohort study. RESULTS: Physiologic outcome parameters maximal workload (MWL), left ventricular ejection fraction (LVEF) and pressure-heart rate product increase (PHRPI) at 50 W ergometric exercise improved more in active treatment than in placebo patients. Magnitude of improvement was independent from baseline for LVEF but increased for MWL and PHRPI with baseline severity. Improvement of typical symptoms like reduced exercise tolerance, exertional dyspnea, weakness, fatigue, and palpitations improved more with active treatment and in patients with more severe symptoms. A weak association between improvements in MWL, PRHP, and symptoms could be demonstrated. Gender differences in treatment effects could be explained by baseline differences. Results of the pooled analysis are in agreement with observations in the cohort study. CONCLUSIONS: Crataegus extract treatment effects on physiologic outcomes and typical symptoms were modulated by baseline severity. Taking baseline differences into account, benefits were comparable in male and female patients with impaired exercise-tolerance in early chronic heart-failure.

Therapeutic implications of the gender-specific aspects of cardiovascular disease.

The manifestations of cardiovascular diseases differ between men and women, as do outcomes after therapeutic interventions. It is important that those involved in drug discovery and development, as well as disease treatment, are aware of these differences because such variations are likely to have an increasing role in therapeutic decisions in the future. Here, I review gender differences in the most frequent cardiovascular diseases and their underlying sex-dependent molecular pathophysiology, and discuss gender-specific effects of current cardiovascular drugs and the implications for novel strategies for drug development.