Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis.

Nitro-oleic acid (NO2-OA), a nitric oxide (NO)- and nitrite (NO2-)-derived electrophilic fatty acid metabolite, displays anti-inflammatory and anti-fibrotic signaling actions and therapeutic benefit in murine models of ischemia-reperfusion, atrial fibrillation, and pulmonary hypertension. Muscle LIM protein-deficient mice (Mlp-/-) develop dilated cardiomyopathy (DCM), characterized by impaired left ventricular function and increased ventricular fibrosis at the age of 8 weeks. This study investigated the effects of NO2-OA on cardiac function in Mlp-/- mice both in vivo and in vitro. Mlp-/- mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneous osmotic minipumps. Wildtype (WT) littermates treated with vehicle served as controls. Mlp-/- mice exhibited enhanced TGFß signalling, fibrosis and severely reduced left ventricular systolic function. NO2-OA treatment attenuated interstitial myocardial fibrosis and substantially improved left ventricular systolic function in Mlp-/- mice. In vitro studies of TGFß-stimulated primary cardiac fibroblasts further revealed that the anti-fibrotic effects of NO2-OA rely on its capability to attenuate fibroblast to myofibroblast transdifferentiation by inhibiting phosphorylation of TGFß downstream targets. In conclusion, we demonstrate a substantial therapeutic benefit of NO2-OA in a murine model of DCM, mediated by interfering with endogenously activated TGFß signaling.

Hematopoietic PI3Kδ deficiency aggravates murine atherosclerosis through impairment of regulatory T cells.

Chronic activation of the adaptive immune system is a hallmark of atherosclerosis. As PI3Kδ is a key regulator of T and B-cell differentiation and function, we hypothesized that alleviation of adaptive immunity by PI3Kδ inactivation may represent an attractive strategy counteracting atherogenesis. As expected, lack of hematopoietic PI3Kδ in atherosclerosis-prone Ldlr-/- mice resulted in hindered T- and B-cell numbers, CD4+ effector T cells, Th1 response, and immunoglobulin levels. However, despite markedly impaired peripheral proinflammatory Th1 cells and atheromatous CD4+ T cells, the unexpected net effect of hematopoietic PI3Kδ deficiency was aggravated vascular inflammation and atherosclerosis. Further analyses revealed that PI3Kδ deficiency impaired numbers, immunosuppressive functions, and stability of regulatory CD4+ T cells (Tregs), whereas macrophage biology remained largely unaffected. Adoptive transfer of wild-type Tregs fully restrained the atherosclerotic plaque burden in Ldlr-/- mice lacking hematopoietic PI3Kδ, whereas PI3Kδ deficient Tregs failed to mitigate disease. Numbers of atheroprotective B-1 and proatherogenic B-2 cells as well serum immunoglobulin levels remained unaffected by adoptively transferred wild-type Tregs. In conclusion, we demonstrate that hematopoietic PI3Kδ ablation promotes atherosclerosis. Mechanistically, we identified PI3Kδ signaling as a powerful driver of atheroprotective Treg responses, which outweigh PI3Kδ driven proatherogenic effects of adaptive immune cells like Th1 cells.

Acute Chest Pain­Diagnostic Accuracy and Pre-Hospital Use of Anticoagulants and Platelet Aggregation Inhibitors

BACKGROUND: Acute chest pain (aCP) can be a symptom of life-threatening diseases such as acute coronary or aortic syndrome, but often has a non-cardiac cause. The recommendations regarding pre-hospital drug treatment of patients with aCP are ambiguous. METHODS: A retrospective cohort study was conducted of 822 patients with aCP who were attended by emergency physicians. The cause of aCP was classified as follows: acute coronary syndrome without ST-segment elevation (NSTE-ACS), acute aortic syndrome, hypertensive crisis, cardiac arrhythmias, musculoskeletal, or other. The suspected and discharge diagnoses were compared, and the pre-hospital administration of acetylsalicylic acid (ASA) and unfractionated heparin (UFH) was analyzed. Furthermore, the parameters that improved diagnostic accuracy were investigated. RESULTS: The positive predictive value of the diagnosis assigned by the emergency physician (EP diagnosis) was 39.7%. NSTEACS was the most commonly suspected cause of aCP (74.7%), but was confirmed after hospital admission in only 26.3% of patients. ASA was administered in 51%, UFH in 55%, and both substances in 46.4% of cases. A large proportion of patients received anticoagulants in the pre-hospital setting although the discharge diagnosis was not NSTE-ACS: ASA 62.9%, UFH 66.0%, both substances 56.5%. CONCLUSION: ASA and UFH are often given to EP-accompanied patients with aCP despite the low accuracy of diagnosis in the pre-hospital setting. Pre-hospital measurement of high-sensitivity troponin T (hs Trop-T) might improve discrimination between NSTE-ACS and other causes of aCP. This is important, as the current guidelines contain no clear recommendations for prehospital drug treatment in NSTE-ACS.

How long is long enough? Good neurologic outcome in out-of-hospital cardiac arrest survivors despite prolonged resuscitation: a retrospective cohort study.

BACKGROUND: Despite all efforts, mortality of out of hospital cardiac arrest (OHCA) remains high. Patients with OHCA due to a primary shockable rhythm typically have a better prognosis. However, outcome worsens if return of spontaneous circulation (ROSC) cannot be achieved quickly. There is insufficient evidence for maximum duration of resuscitation in these patients and it is unclear, which patients profit from transport under ongoing CPR. OBJECTIVE: Investigate predictors for favourable neurologic outcome in OHCA patients with presumed cardiac cause due to refractory shockable rhythm (rSR). METHODS: Retrospective analysis of OHCA patients that presented to a tertiary hospital due to a rSR. RESULTS: One hundred seventy-five OHCA patients with presumed cardiac cause due to rSR were included. Overall hospital mortality was 50% and 83% of initial survivors were discharged with a good neurologic outcome [cerebral performance category (CPC) 1-2]. In patients with a time from cardiac arrest to ROSC of > 45 min, 18% survived to CPC 1-2. Independent predictors for good neurologic outcome were age, lower no-flow time and lower serum lactate levels at hospital arrival. CONCLUSION: In an urban setting, a significant proportion of OHCA patients with rSR can survive to a good neurologic outcome, despite very long time to ROSC.