Preconditioning with selective autoretroperfusion: In vivo and in silico evidence of washout hypothesis.

Introduction: Prompt reperfusion of coronary artery after acute myocardial infarction (AMI) is crucial for minimizing heart injury. The myocardium, however, may experience additional injury due to the flow restoration itself (reperfusion injury, RI). The purpose of this study was to demonstrate that short preconditioning (10 min) with selective autoretroperfusion (SARP) ameliorates RI, based on a washout hypothesis. Methods: AMI was induced in 23 pigs (3 groups) by occluding the left anterior descending (LAD) artery. In SARP-b (SARP balloon inflated) and SARP-nb (SARP balloon deflated) groups, arterial blood was retroperfused for 10 min via the great cardiac vein before releasing the arterial occlusion. A mathematical model of coronary circulation was used to simulate the SARP process and evaluate the potential washout effect. Results: SARP restored left ventricular function during LAD occlusion. Ejection fraction in the SARP-b group returned to baseline levels, compared to SARP-nb and control groups. Infarct area was significantly larger in the control group than in the SARP-b and SARP-nb groups. End-systolic wall thickness was preserved in the SARP-b compared to the SARP-nb and control groups. Analyte values (pH, lactate, glucose, and others), measured every 2 min during retroperfusion, suggest a "washout" effect as one important mechanism of action of SARP in reducing infarct size. With SARP, the values progressively approached baseline levels. The mathematical model also confirmed a possible washout effect of tracers. Discussion: RI can be ameliorated by delaying restoration of arterial flow for a brief period of time while pretreating the infarction with SARP to restore homeostasis via a washout mechanism.

The dilated coronary sinus: utility of coronary sinus cross-sectional area and eccentricity index in differentiating right atrial pressure overload from persistent left superior vena cava.

BACKGROUND: Pulmonary hypertension and right atrial pressure overload (RAPO) cause dilation of the coronary sinus (CS). Persistent connection of the left superior vena cava (LSVC) to the CS is another cause of CS dilation. The purpose of this study was to evaluate the usefulness of coronary sinus cross-sectional area (CSA) and eccentricity index (EI) in differentiating persistent LSVC from right heart overload and RAPO in patients with dilated CS. METHODS: We identified 15 patients with a dilated CS by echocardiography. Offline analysis was used to measure CS-CSA and CS-EI at end-diastole in the parasternal long axis plane. EI was defined as B/A, where A is the widest diameter and major axis of the CS, and B is the diameter of the minor axis (perpendicular to and bisecting A at its midpoint). Persistent LSVC was confirmed by either computed tomography or injection of agitated saline in the left antecubital vein. RESULTS: CS-CSA was significantly larger in PLSVC group than in group with RAPO. Also, CS-EI was lower in PLSVC than in RAPO group (P = 0.0003). EI was the most sensitive and specific discriminator between patients with persistent LSVC vs. RAPO. CS-EI was <0.8 in all PLSVC patients and >0.8 in all RAPO patients (sensitivity and specificity = 100%). CONCLUSION: Patients with persistent LSVC have a significantly higher CS-CSA than those with elevated RA pressure. When dilated CS is present, a CS-EI <0.8 is 100% sensitive and specific for persistent LSVC. Thus, the CS-EI can be used in cases of dilated CS to diagnose the presence of persistent LSVC with a very high degree of certainty, and can help differentiate this congenital anomaly from RAPO.

The effect of Ting point (tendinomuscular meridians) electroacupuncture on thermal pain: a model for studying the neuronal mechanism of acupuncture analgesia.

OBJECTIVE: The aim of this study was to characterize the role of Ting points (TP) in acute pain management and its potential use in functional imaging studies by quantitatively assessing: (1) the change in peripheral thermal thresholds before and after the electroacupuncture (EA); and (2) the corresponding behavioral feedback of thermal pain stimulation and the de qi sensation of EA. DESIGN: The study design was prospective. SETTINGS/LOCATION: Healthy subjects were recruited for the study at the University of California, San Diego Medical Center. SUBJECTS/INTERVENTIONS: Thirteen (13) healthy subjects were studied. Baseline thermal thresholds (cold and warm sensations and cold and hot pain) were measured at premarked testing sites along the medial aspects of bilateral lower extremities. Five (5) seconds of hot pain (HP) was delivered to the testing sites and the corresponding pain visual analog scale (VAS) scores were recorded. Thirty (30) seconds of EA was delivered via the SP1 and LR1 on the left lower extremities at 5 Hz via a 6-V square-wave stimulator. OUTCOME MEASURES: The VAS scores of the HP and de qi sensation (tingling) during the EA were recorded. The thermal thresholds and VAS scores for the HP and de qi were obtained immediately and both 30 and 60 minutes after the EA. Adaptation testing was also carried out to assess the change in thermal thresholds and the VAS scores of HP without EA. RESULTS: The warm thresholds of bilateral medial calves significantly increased (p < 0.01) after 30 seconds of EA stimulation. The HP VAS score reduced significantly at the ipsilateral calf during EA in comparison to preacupuncture and postacupuncture (p < 0.01) measurements. No significant change in thermal thresholds was noted in the adaptation paradigm. CONCLUSIONS: EA at the TP has an inhibitory effect on the C-fiber afferents. The analgesic benefit observed is most likely A-delta afferent mediated. Further correlation studies in functional imaging may provide defining data for the observed analgesic mechanism.

Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia.

A classical cellular response to hypoxia is a cessation of growth. Hypoxia-induced growth arrest differs in different cell types but is likely an essential aspect of the response to wounding and injury. An important component of the hypoxic response is the activation of the hypoxia-inducible factor 1 (HIF-1) transcription factor. Although this transcription factor is essential for adaptation to low oxygen levels, the mechanisms through which it influences cell cycle arrest, including the degree to which it cooperates with the tumor suppressor protein p53, remain poorly understood. To determine broadly relevant aspects of HIF-1 function in primary cell growth arrest, we examined two different primary differentiated cell types which contained a deletable allele of the oxygen-sensitive component of HIF-1, the HIF-1alpha gene product. The two cell types were murine embryonic fibroblasts and splenic B lymphocytes; to determine how the function of HIF-1alpha influenced p53, we also created double-knockout (HIF-1alpha null, p53 null) strains and cells. In both cell types, loss of HIF-1alpha abolished hypoxia-induced growth arrest and did this in a p53-independent fashion. Surprisingly, in all cases, cells lacking both p53 and HIF-1alpha genes have completely lost the ability to alter the cell cycle in response to hypoxia. In addition, we have found that the loss of HIF-1alpha causes an increased progression into S phase during hypoxia, rather than a growth arrest. We show that hypoxia causes a HIF-1alpha-dependent increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27; we also find that hypophosphorylation of retinoblastoma protein in hypoxia is HIF-1alpha dependent. These data demonstrate that the transcription factor HIF-1 is a major regulator of cell cycle arrest in primary cells during hypoxia.