Ray Chu-Jeng Chiu

Transcoronary implantation of bone marrow stromal cells ameliorates cardiac function after myocardial infarction

OBJECTIVESnBone marrow stromal cells are capable of differentiating into cardiomyogenic cells. We tested the hypothesis that transcoronary implantation of bone marrow stromal cells may regenerate infarcted myocardium and reduce cardiac dysfunction.nnnMETHODSnIsolated bone marrow stromal cells from the isogenic donor rats were transfected with LacZ reporter gene for cell labeling. To induce cardiomyogenic differentiation, the bone marrow stromal cells were treated with 5-azacytidine before implantation. Two weeks after left coronary ligation, these cells (1 x 10(6) in 150 microL) were infused into the briefly distally occluded ascending aorta of the recipient rats (n = 15) to simulate direct coronary infusion clinically. Control animals were infused with cell-free medium (n = 14). Cardiac function was evaluated by echocardiography at preimplantation and 4 and 8 weeks postimplantation. The hearts were then immunohistochemically studied to identify phenotypic changes of implanted bone marrow stromal cells.nnnRESULTSnImmediately after cell infusion, the bone marrow stromal cells were trapped within coronary vessels in both infarcted and noninfarcted areas. However, after 8 weeks, most of the cells were identified in the scar and periscar tissue, expressing sarcomeric myosin heavy chain and cardiomyocyte-specific protein troponin I-C. Some bone marrow stromal cells were found to be connected to the adjacent host cardiomyocytes with gap junction. Two-way repeated-measures analysis of variance revealed significant improvement in fractional shortening and end-diastolic and end-systolic diameter of the left ventricle (P =.0465,.002,.0004, respectively) in the bone marrow stromal cell group.nnnCONCLUSIONSnAlthough bone marrow stromal cells had been reported to improve cardiac function when injected directly into the myocardial scar, this study demonstrated for the first time that bone marrow stromal cells can be delivered via the coronary artery, as they are capable of targeted migration and differentiation into cardiomyocytes in the scar tissue to improve cardiac function.

Retrograde Coronary Sinus Perfusion for Myocardial Protection during Cardiopulmonary Bypass

The pathophysiology of retrograde coronary sinus perfusion was studied in a vented, nonworking heart in vitro. The fraction of nutritional blood flow, estimated with the trapping index of radioactive microspheres (15 +/- 5 mu), is approximately one-fifth of total flow. The funoff is primarily through the thebesian system and venovenous channels, as is shown with Microfil injection studies. These results suggest that retrograde coronary sinus perfusion would be of marginal value in revascularizing a working heart but would be effective in protecting a hypothermic, nonworking myocardium. Canine experiments indicate that retrograde coronary sinus perfusion can provide efficient core cooling of the myocardium during cardiopulmonary bypass even in the presence of complete coronary artery occlusion. It is technically simple, delivers cardioplegic solutions to the myocardium without the risk of coronary ostial injury, and can be employed in the presence of severe aortic insufficiency and open aortic root. Retrograde coronary sinus perfusion therefore appears to be a valuable alternative mode of myocardial protection during cardiac operations.

Misleading “Pulmonary Wedge Pressure” after Pneumonectomy: Its Importance in Postoperative Fluid Therapy

Patients who have undergone pneumonectomy are reported to be at increased risk of serious pulmonary edema. Monitoring fluid therapy using the Swan-Ganz balloon-tipped catheter is therefore important in the perioperative management of these patients. Pulmonary artery occlusion pressure (PAOP), determined by inflating a balloon to occlude a branch of the pulmonary artery, is routinely used to measure pulmonary wedge pressure (PWP). In turn, PWP reflects left atrial pressure (LAP). We clinically observed postpneumonectomy patients in whom pulmonary edema developed, but whose PAOP was near normal. Our findings led us to suspect that PAOP in such patients may reflect a falsely low PWP value. We hypothesized that after pneumonectomy inflation of the balloon on the Swan-Ganz catheter to obtain PWP can result in considerable occlusion of the remaining cross-sectional area of pulmonary circulation. This occlusion acutely increases the right ventricular afterload, resulting in reduced cardiac output and reduced LAP. Although the PAOP under these circumstances still accurately reflects the LAP, these values have been artificially lowered; hence, they result in falsely low PWP readings. To verify this hypothesis, the following canine experiments were performed. Five dogs were monitored with a Swan-Ganz catheter, a left atrial catheter, and an electromagnetic flow probe applied to a carotid artery. Before pneumonectomy, inflation of the balloon to obtain PAOP caused no statistically significant change in LAP or carotid flow, and PAOP was identical to both LAP and PWP. (PWP was determined by advancing and wedging the pulmonary artery catheter tip into a peripheral branch without inflating the balloon.(ABSTRACT TRUNCATED AT 250 WORDS)

The Importance of Monitoring Intramyocardial Temperature during Hypothermic Myocardial Protection

In 50 patients undergoing cardiac operation, hypothermic cardioplegic solution was infused into the root of the aorta immediately after aortic cross-clamping. Cardiac standstill was achieved within 1 to 3 minutes. However, monitoring of intramyocardial temperature with a needle thermistor revealed that such core cooling is unpredictable (the intramyocardial temperature achieved ranged from 7 degrees to 33 degrees C), unstable (this temperature can rise at more than 0.5 degrees C per minute), and uneven (a difference of up to 17 degrees C was observed between the intramyocardial temperature of the anterior and posterior left ventricular sites). The area supplied by the stenotic coronary artery was least protected. Monitoring of intramyocardial temperature enables one to know when supplementary cooling is indicated. We conclude that widespread differences in this temperature during cardiac operation make monitoring advisable for optimal myocardial protection.

Complement (C3, C4) Consumption in Cardiopulmonary Bypass, Cardioplegia, and Protamine Administration

Anaphylatoxins produced by complement activation have been postulated to be responsible for postperfusion syndrome and protamine hypotension in patients undergoing cardiac surgical procedures. The consumption of serum complement components C3 and C4, which reflects the classic and alternate pathway activations of the complement system, was studied in 22 patients undergoing cardiac operations. Prior to the onset of cardiopulmonary bypass, the complement levels were within normal range. Rapid reduction in both C3 and C4 within minutes of cardiopulmonary bypass indicated rapid complement activation. Such a reduction in complement levels could not be accounted for by either hemodilution or transfusion of complement-poor blood. Aortic cross-clamping and cold potassium cardioplegia followed by myocardial reperfusion did not lead to further consumption of C3 and C4. Slow intravenous infusion of protamine sulfate after cardiopulmonary bypass did not change C3 and C4 levels significantly in our patients, although protamine and heparin-protamine complex have been shown to activate complement components in vitro. In another group of 9 similar cardiac surgical patients, C3 and C4 were found to return to normal levels within 24 hours after operation. This study thus confirms the rapid activation of the complement system by cardiopulmonary bypass but fails to demonstrate further activation of the complement system by cardioplegia or protamine administration.

Adult stem cell therapy for heart failure

Evidence indicates that bone marrow and many other somatic tissues contain pluripotent or multipotent adult stem cells as well as progenitor cells which can differentiate into cells of various phenotypes. Experimental studies strongly suggest that the normal function of the marrow derived adult stem cells is for tissue repair, and that they can be recruited by signals originating from injured tissue, traffic through the circulation and home into the injured site to undergo milieu dependent differentiation in situ. In the heart, these cells may differentiate into cardiomyocytes, vascular cells and scar tissue, thus participating in vasculogenesis, scar maturation and modulation of the remodelling process of the myocardium. To augment such a healing process, cell therapy using such cells, which may be preprogrammed if desired, may have donor cells implanted by direct injection, coronary infusion and, in some cases, by systemic intravenous administration. Improved ventricular function has been reported in myocardial infarct animal models. Although early Phase I clinical trials have been initiated for both autologous myoblast and autologous marrow cell transplants with favourable reported outcomes, the data are still too preliminary to draw definitive conclusions regarding their safety and efficacy. Additional mechanistic and translational preclinical investigations are essential, and well designed clinical studies are required before the great potential of adult stem cell therapy can be fully realised and benefit the vast number of heart failure patients.

Hemodynamic responses to sepsis: Hypodynamic versus hyperdynamic states

Abstract It has never been fully understood why the circulatory responses of some septic patients and experimental septic animal models are hyperdynamic, while others are hypodynamic, the latter often thought to reflect an “overwhelming” sepsis. This study identifies the “focus of infection” as the central factor which governs the host response to sepsis. Similar hosts (piglets) received the same bacteria (Escherichia coli strain U9-41) in comparable doses, by two different routes, one intravenous and the other intramuscular. The intravenous group did not have a focus of infection and developed hypodynamic shock (low cardiac output, hypothermia, leukopenia). The low flow state was not preceded by a high output phase and was not reversed by increasing the preload, indicating myocardial depression. The intramuscular group, with a focus of infection and inflammation, developed a hyperdynamic state (high cardiac output, fever, and leukocytosis). The important pathophysiologic role of a focus of infection should be recognized, particularly in devising experimental models to study septic shock.

Predictive power of penile/brachial index in diagnosing male sexual impotence

To evaluate the diagnostic power of penile/brachial index (PBI) in patients studied for male sexual impotence, we prospectively interviewed 503 patients referred to our vascular laboratory for PBI measurements. Since the predictive values of diagnostic tests are affected by the prevalence of the disease in the population studied, we calculated the independent likelihood ratio for various PBI levels obtained. For the purpose of this analysis, organic impotence was defined as occurring in patients who had no nocturnal erections, whereas clinical impotence was defined as occurring in those patients who could not achieve penetration during intercourse. The patients were divided into four groups by the presence or absence of risk factors, including peripheral vascular disease (PVD) and diabetes mellitus. Patients taking medications that may affect potency (n = 175) were excluded from this analysis. The results show that the predictive power of PBI is less in diabetic patients with PVD and least in those without either PVD, diabetes, or drugs. In patients with PVD but no other risk factors, PBI is highly diagnostic with a sharp cut-off point at 0.6. Thus, the diagnostic power of PBI can be improved by considering the risk factors in the patients studied.

Pulmonary Reperfusion Syndrome

Reperfusion syndrome of the lung may play a role in the pulmonary edema and hemorrhage that occur following pulmonary embolectomy, cardiopulmonary bypass, and shock. Bioenergetic, metabolic, and ultrastructural studies of canine lungs indicate that ventilated lung tissue could tolerate 5 hours of pulmonary arterial occlusion with minimal damage. However, a 24-hour interruption of pulmonary arterial blood flow produced a significant decrease in the ratio of adenosine triphosphate to adenosine disphosphate, and glycogen, and an increase in tissue lactate. Reperfusion of these lungs resulted in even more pronounced biochemical and ultrastructural deterioration, as well as gross pulmonary edema and hemorrhage. The lesion appears to be similar to the reperfusion damage that occurs in other organs, such as the kidney, and the skeletal and cardiac muscles.

The Rationale for Skeletal‐Muscle‐Powered Counterpulsation Devices: An Overview

Two approaches have been taken to managing patients with severe myocardial dysfunction who can no longer be adequately treated with conventional medical and surgical therapies. The first is the biological approach to cardiac transplantation, both orthotopic and parallel heart allografts. The second is the mechanical approach, including the total artificial heart and various left ventricular assist devices (LVADs). Both lines of research have culminated in clinical application in recent years, and increasing numbers of patients benefit from these new developments. However, various lirnitations of these approaches are also becoming apparent. At present, with the recent advance in immunosuppressive therapy, cardiac transplantation offers the best hope for these patients. However, this method is severely limited by the availability of donors. In one estimate, no more than 500 cardiac donors will be available each year in the United States in the foreseeable future. The new immunosuppression drug, Cyclosporin, is now known to cause serious side effects, including renal toxicity, hypertension, and lymphomas. Thus, the impact of cardiac transplantation, epidemiologically speaking, can be expected to remain limited.