Daniel C. Lee

MASP-2 activation is involved in ischemia-related necrotic myocardial injury in humans

BACKGROUND/OBJECTIVES Insufficient blood supply to the heart results in ischemic injury manifested clinically as myocardial infarction (MI). Following ischemia, inflammation is provoked and related to the clinical outcomes. A recent basic science study indicates that complement factor MASP-2 plays an important role in animal models of ischemia/reperfusion injury. We investigated the role of MASP-2 in human acute myocardial ischemia in two clinical settings: (1) Acute MI, and (2) Open heart surgery. METHODS A total of 187 human subjects were enrolled in this study, including 50 healthy individuals, 27 patients who were diagnosed of coronary artery disease (CAD) but without acute MI, 29 patients with acute MI referred for coronary angiography, and 81 cardiac surgery patients with surgically-induced global heart ischemia. Circulating MASP-2 levels were measured by ELISA. RESULTS MASP-2 levels in the peripheral circulation were significantly reduced in MI patients compared with those of healthy individuals or of CAD patients without acute MI. The hypothesis that MASP-2 was activated during acute myocardial ischemia was evaluated in cardiac patients undergoing surgically-induced global heart ischemia. MASP-2 was found to be significantly reduced in the coronary circulation of such patients, and the reduction of MASP-2 levels correlated independently with the increase of the myocardial necrosis marker, cardiac troponin I. CONCLUSIONS These results indicate an involvement of MASP-2 in ischemia-related necrotic myocardial injury in humans.

A Programmable Laboratory Testbed in Support of Evaluation of Functional Brain Activation and Connectivity

An important determinant of the value of quantitative neuroimaging studies is the reliability of the derived information, which is a function of the data collection conditions. Near infrared spectroscopy (NIRS) and electroencelphalography are independent sensing domains that are well suited to explore principal elements of the brains response to neuroactivation, and whose integration supports development of compact, even wearable, systems suitable for use in open environments. In an effort to maximize the translatability and utility of such resources, we have established an experimental laboratory testbed that supports measures and analysis of simulated macroscopic bioelectric and hemodynamic responses of the brain. Principal elements of the testbed include 1) a programmable anthropomorphic head phantom containing a multisignal source array embedded within a matrix that approximates the background optical and bioelectric properties of the brain, 2) integrated translatable headgear that support multimodal studies, and 3) an integrated data analysis environment that supports anatomically based mapping of experiment-derived measures that are directly and not directly observable. Here, we present a description of system components and fabrication, an overview of the analysis environment, and findings from a representative study that document the ability to experimentally validate effective connectivity models based on NIRS tomography.

Traumatic Ventricular Septal Defect

Traumatic ventricular septal defect (VSD) is an uncommon occurrence in cases of penetrating cardiac injury with an incidence of only 1% to 5%. The mainstay of diagnosis of VSDs is the transthoracic echocardiogram. We report a case of an occult traumatic VSD, which was not seen on echocardiography, but was later found on a high-resolution computed tomographic scan of the chest.Traumatic ventricular septal defect (VSD) is an uncommon occurrence in cases of penetrating cardiac injury with an incidence of only 1% to 5%. The mainstay of diagnosis of VSDs is the transthoracic echocardiogram. We report a case of an occult traumatic VSD, which was not seen on echocardiography, but was later found on a high-resolution computed tomographic scan of the chest.

Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury

The pathophysiology of myocardial injury that results from cardiac ischemia and reperfusion (I/R) is incompletely understood. Experimental evidence from murine models indicates that innate immune mechanisms including complement activation via the classical and lectin pathways are crucial. Whether factor B (fB), a component of the alternative complement pathway required for amplification of complement cascade activation, participates in the pathophysiology of myocardial I/R injury has not been addressed. We induced regional myocardial I/R injury by transient coronary ligation in WT C57BL/6 mice, a manipulation that resulted in marked myocardial necrosis associated with activation of fB protein and myocardial deposition of C3 activation products. In contrast, in fB-/- mice, the same procedure resulted in significantly reduced myocardial necrosis (% ventricular tissue necrotic; fB-/- mice, 20 ± 4%; WT mice, 45 ± 3%; P < 0.05) and diminished deposition of C3 activation products in the myocardial tissue (fB-/- mice, 0 ± 0%; WT mice, 31 ± 6%; P<0.05). Reconstitution of fB-/- mice with WT serum followed by cardiac I/R restored the myocardial necrosis and activated C3 deposition in the myocardium. In translational human studies we measured levels of activated fB (Bb) in intracoronary blood samples obtained during cardio-pulmonary bypass surgery before and after aortic cross clamping (AXCL), during which global heart ischemia was induced. Intracoronary Bb increased immediately after AXCL, and the levels were directly correlated with peripheral blood levels of cardiac troponin I, an established biomarker of myocardial necrosis (Spearman coefficient = 0.465, P < 0.01). Taken together, our results support the conclusion that circulating fB is a crucial pathophysiological amplifier of I/R-induced, complement-dependent myocardial necrosis and identify fB as a potential therapeutic target for prevention of human myocardial I/R injury.

Compartment Syndrome After Endoscopic Harvest of the Great Saphenous Vein During Coronary Artery Bypass Grafting

Compartment syndrome is a limb-threatening condition often associated with traumatic, crush, burn, and reperfusion injuries. It is characterized by the development of disproportionately severe pain, paresthesias, decreased range of motion, loss of pulse, and a tense, edematous limb. In addition, measured compartment pressures and creatine phosphokinase values are often elevated. The definitive treatment is a decompressive fasciotomy. Compartment syndrome after coronary artery bypass grafting, however, is rare. The few reported cases all occurred in the vein donor leg after open harvest. We present a patient with compartment syndrome after endoscopic harvest of the saphenous vein for coronary artery bypass grafting.

Deficiency of complement factor MBL in a patient required cardiac surgery after an acute myocardial infarction with underlining chronic lymphocytic leukemia

Increasing evidence suggests that Mannan-binding lectin (MBL), the initial factor of the lectin pathway of complement, plays a role in cardiovascular diseases, i.e. inversely associated with risk of myocardial infarction (MI). In the present case, a patient with MBL deficiency underwent coronary artery bypass grafting (CABG) after an acute MI with underlining chronic lymphocytic leukemia (CLL). Post-operatively, the patient had a cerebral vascular accident and eventually expired. Analysis of his blood samples from pre-, intra-, and post-operative periods showed that MBL levels abruptly increased post-operatively. We hypothesize that the post-operative increase of MBL in the patient with pre-existing MBL deficiency may contribute to systemic inflammation, causing a detrimental effect after cardiac surgery.

On the geometry dependence of differential pathlength factor for near-infrared spectroscopy. I. Steady-state with homogeneous medium

Abstract. This work analytically examines some dependences of the differential pathlength factor (DPF) for steady-state photon diffusion in a homogeneous medium on the shape, dimension, and absorption and reduced scattering coefficients of the medium. The medium geometries considered include a semi-infinite geometry, an infinite-length cylinder evaluated along the azimuthal direction, and a sphere. Steady-state photon fluence rate in the cylinder and sphere geometries is represented by a form involving the physical source, its image with respect to the associated extrapolated half-plane, and a radius-dependent term, leading to simplified formula for estimating the DPFs. With the source-detector distance and medium optical properties held fixed across all three geometries, and equal radii for the cylinder and sphere, the DPF is the greatest in the semi-infinite and the smallest in the sphere geometry. When compared to the results from finite-element method, the DPFs analytically estimated for 10 to 25 mm source–detector separations on a sphere of 50 mm radius with μa=0.01  mm−1 and μs′=1.0  mm−1 are on average less than 5% different. The approximation for sphere, generally valid for a diameter ≥20 times of the effective attenuation pathlength, may be useful for rapid estimation of DPFs in near-infrared spectroscopy of an infant head and for short source–detector separation.

Off-Pump versus On-Pump Coronary Artery Bypass Grafting in Octogenarians: Comparison of Short-Term Outcomes and Long-Term Survival

Off-pump coronary artery bypass (OPCAB) has gained increasing acceptance with potential benefits for high-risk elderly patients. We report a surgeons operative outcomes in octogenarians with an OPCAB program. Retrospective, intention-to-treat analysis of 97 consecutive octogenarians who underwent coronary bypass by a single surgeon between 1997 and 2001 before and after initiation of a multi-vessel OPCAB program was performed. OPCAB was attempted in all octogenarians. The OPCAB cohort had higher serum creatinine (OPCAB vs. pre-OPCAB: 1.30 ± 0.79 mg/dl vs. 1.08 ± 0.27, p = 0.04) and ejection fractions (52 ± 14% vs. 45 ± 11%, p = 0.02) than the pre-OPCAB cohort. The OPCAB group was more likely to require urgent/emergency surgery (63 vs. 40%, p = 0.04) and to have chronic renal insufficiency (18 vs. 3%, p = 0.05). After programmatic change to OPCAB, significant postoperative improvements were observed in the length of hospital stay (17 ± 19 vs. 8 ± 4 days, p < 0.01), duration of inotropic requirement (47 ± 70 vs. 18 ± 39 h, p < 0.04), duration of ventilator support (51 ± 54 vs. 16 ± 27 h, p < 0.01) and incidence of tracheostomy (16 vs. 3%, p < 0.02). In-hospital mortalities (3.2 vs. 2.7%), strokes (3 per group) and 5-year survival did not differ significantly (57 vs. 67%, p = 0.50, NS). Despite some higher preoperative risks, the OPCAB program demonstrated clinical benefits in octogenarians but no advantage in hospital-mortality or long-term survival.

How does the differential pathlength factor for steady-state near-infrared spectroscopy of homogeneous medium vary with geometry?

We estimate analytically how much the differential pathlength factor for steady-state near-infrared spectroscopy of homogeneous medium varies when evaluated in geometries including sphere as applying to neonatal head, comparing to that in the semi-infinite half-space.

Perioperative mannan-binding lectin (MBL) patterns in cardiac surgery may correlate with the clinical outcomes in MBL deficient patients.

Previously we reported a case of abrupt change of postoperative mannan-binding-lectin (MBL) in a patient with preexisting MBL deficiency who expired shortly after cardiac surgery. Herein we report additional cases of 3 more patients with preexisting MBL deficiency who underwent cardiac surgery. Analysis of their blood samples from the perioperative period showed their MBL levels were abruptly increased at 24 hours after surgery. However, 2 patients had a subsequent drop of MBL at 48 hours, and both expired. These data indicated that the postoperative decrease of MBL may have been related with an unfavorable outcome after cardiac surgery.