Reperfusion injury following acute myocardial infarction is associated with significant morbidity. Activation of neuronal or non-neuronal cholinergic pathways in the heart has been shown to reduce ischemic injury, and this effect has been attributed primarily to muscarinic acetylcholine receptors. In contrast, the role of nicotinic receptors, specifically α-7 subtype (α7nAChR), in the myocardium remains unknown, which offers an opportunity to potentially repurpose several agonists/modulators that are currently under development for neurologic indications. Treatment of ex vivo and in vivo rat models of cardiac ischemia/reperfusion (I/R) with a selective α7nAChR agonist (GTS21) showed significant increases in left ventricular developing pressure and rates of pressure development, without effects on heart rate. These positive functional effects were blocked by co-administration with methyllycaconitine (MLA), a selective antagonist of α7nAChRs. In vivo, delivery of GTS21 at the initiation of reperfusion reduced infarct size by 42% (p < 0.01) and decreased tissue reactive oxygen species (ROS) by 62% (p < 0.01). Flow cytometry of MitoTracker Red-stained mitochondria showed that mitochondrial membrane potential was normalized in mitochondria isolated from GTS21-treated compared with untreated I/R hearts. Intracellular adenosine triphosphate (ATP) concentration in cultured cardiomyocytes exposed to hypoxia/reoxygenation was reduced (p < 0.001), but significantly increased to normoxic levels with GTS21 treatment, which was abrogated by MLA pretreatment. Activation of stress-activated kinases JNK and p38MAPK was significantly reduced by GTS21 in I/R. We conclude that targeting myocardial α7nAChRs in I/R may provide therapeutic benefit by improving cardiac contractile function through a mechanism that preserves mitochondrial membrane potential, maintains intracellular ATP and reduces ROS generation, thus limiting infarct size. online address: http://www.molmed.org
Background: Impact of mechanical left ventricular (LV) unloading on myocardial tissue perfusion and its regulating factors remain unclear. This study was conducted to elucidate the predictors of regional blood flow (RBF) improvement by mechanical LV unloading.Materials and Methods: One to four weeks after percutaneous induction of myocardial infarction (MI), Yorkshire pigs (n = 15) underwent mechanical LV unloading using Impella CP. Hemodynamic parameters were collected prior to LV unloading. RBF in infarct, border and remote myocardium were measured by fluorescent microsphere injections before and 120 min after LV unloading.Results: RBF showed variable responses to mechanical LV unloading. While infarct RBF improved in general (0.33 ± 0.13 to 0.42 ± 0.19 mL/min/g, p = 0.06), there were a few pigs that showed little improvement. Meanwhile, there were no clear trends in the border (1.07 ± 0.47 to 1.02 ± 0.65 mL/min/g, p = 0.73) and remote myocardial RBF (1.25 ± 0.52 to 1.23 ± 0.68 mL/min/g, p = 0.85). In the simple linear regression analysis, cardiac output, mean pulmonary arterial wedge pressure, mean left atrial pressure, minimum LV pressure, end-diastolic LV pressure, maximum dP/dt, slope of end-diastolic pressure-volume relationship (EDPVR) and end-diastolic wall stress were significantly associated with % change of infarct RBF. In the multiple regression model, slope of EDPVR and maximum dP/dt remained as independent predictors of infarct RBF change.Conclusion: Steeper EDPVR and lower maximum dP/dt were associated with increased blood perfusion in the infarct area after LV unloading. Our data suggests mechanical LV unloading is more beneficial in post-MI patients with high diastolic pressure associated with increased LV stiffness and in those with worse cardiac contractility.
Coronary reperfusion therapy has played a pivotal role for reducing mortality and heart failure after acute myocardial infarction. Although several adjunctive approaches have been studied for reducing infarct size further, both ischemia–reperfusion injury and microvascular obstruction are still major contributors to both early and late clinical events after acute myocardial infarction. The progress in the field of cardioprotection has found several promising proof‐of‐concept preclinical studies. However, translation from bench to bedside has not been very successful. This comprehensive review discusses the importance of infarct size as a driver of clinical outcomes post‐acute myocardial infarction and summarizes recent novel device‐based approaches for infarct size reduction. Device‐based interventions including mechanical cardiac unloading, myocardial cooling, coronary sinus interventions, supersaturated oxygen therapy, and vagal stimulation are discussed. Many of these approaches can modify ischemic myocardial biology before reperfusion and offer unique opportunities to target ischemia–reperfusion injury.
Background: Left atrial (LA) dysfunction is one of the predictive factors of worse outcomes after mitral valve surgery for mitral regurgitation (MR). We aimed to investigate the effect of MR etiology on progression of LA remodeling in swine MR models. Methods: MR was induced in 14 Yorkshire pigs using catheter-based procedures. Seven pigs underwent simultaneous occlusions of the left circumflex artery and the diagonal branch, which resulted in ischemic MR (IMR group). The other seven pigs underwent chordal severing to induce leaflet prolapse simulating degenerative MR (DMR group). Changes in LA volume and function were assessed at baseline, 1 and 3 months using echocardiography and hemodynamic evaluations. Histopathological assessments were conducted to evaluate LA hypertrophy and fibrosis. Results: At 3 months, quantitative MR severity was comparable and severe in both groups. Despite the similar degree of MR, minimum LA volume index increased significantly more in the IMR group (IMR: 11.9±6.4 to 73.2±6.4, DMR: 10.7±6.4 to 29.5±6.4 ml/m2, pinteraction=0.004). Meanwhile, increase in maximum LA volume index was similar between the groups, resulting in lower LA emptying function in the IMR group (IMR: 60.1±3.1 to 29.4±3.1, DMR: 62.4±3.1 to 58.2±3.1%, pinteraction=0.0003). LA reservoir strain assessed by echocardiography was also significantly lower in the IMR group. Histological analyses revealed increased LA cellular hypertrophy and fibrosis in the IMR group. Conclusions: Ischemic MR is associated with aggressive remodeling and reduced emptying function compared to MR due to leaflet prolapse. Earlier intervention might be necessary for ischemic MR to prevent LA remodeling.
The prevalence of CNS involvement of Adamantiadis-Behçet's syndrome (A-Bs) vary widely. Long-term follow-up studies of CNS involvement have rarely been reported. Five patients with CNS involvement, who were followed up from 2 to 9 years, are presented. Clinicolaboratory investigations (cerebrospinal fluid examination, electroencephalogram, brain CAT scan and MRI) were carried out. One patient had four and two patients had two attacks of CNS involvement with various clinical manifestations. The other two patients had a rather chronic course with a single slight CNS attack. Raised proteins and IgG were found in the CSF. Abnormal electroencephalographic findings were detected in three patients. Communicating hydrocephalus and various other abnormalities on CT scan and MRI were noted. All patients received corticosteroids and immunosuppressants during the attack period.
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