Human umbilical cord blood cells: a new alternative for myocardial repair?

Cell therapy for myocardial disease is a rapidly progressive field. However, present strategies of cell transplantation into the infarcted myocardium have limitations from practical points of view. One of the biggest challenges is to achieve a sufficient number of suitable cells. Umbilical cord blood (UCB), an unlimited source of stem/progenitor cells that could be used for transplantation into the injured heart, is readily available. The aim of our review is to describe the potential and prospect of UCB as a new supplier of cells for myocardial repair. The use of UCB stem cells might be of importance to elderly and sick people in whom the availability of autologous stem cells is limited.

Initial experience with multivessel percutaneous coronary intervention during mechanical reperfusion for acute myocardial infarction.

The feasibility and safety of simultaneous multivessel percutaneous coronary intervention during mechanical reperfusion for acute myocardial infarction was analyzed in a retrospective, case-controlled study. Patients who underwent multivessel coronary intervention had a higher risk of adverse clinical outcomes through 6 months compared with matched controls in whom coronary intervention was limited to the infarct-related artery.

Noninvasive assessment of left ventricular end-diastolic pressure by the response of the transmitral a-wave velocity to a standardized Valsalva maneuver.

Impaired relaxation is frequently masked by elevated filling pressures, resulting in a pseudonormal flow pattern (E/A >1.0). Because the E/A wave ratio increases as filling pressures rise, it is generally assumed that patients with an E/A ratio of <1.0 (impaired relaxation pattern) have relatively low filling pressures. Nevertheless, patients with an E/A ratio of <1.0 can have as profoundly elevated filling pressures as patients with a pseudonormal or restrictive filling pattern. Because left ventricular (LV) pressure during end-diastole essentially determines atrial afterload, the response of the A-wave velocity to a reduction of atrial afterload by a standardized Valsalva maneuver should allow estimation of LV end-diastolic pressure (LVEDP) regardless of the baseline Doppler flow pattern. This was tested in 20 consecutive patients who were studied by pulse-wave Doppler echocardiography during cardiac catheterization. There was a close correlation between LVEDP and the change in A-wave velocity during the Valsalva maneuver (r = 0.85, SEE 6.7 mm Hg) regardless of the baseline E/A ratio. In patients with a LVEDP of <15 mm Hg the A wave decreased by 21 +/- 15 cm/s. In patients with a LVEDP of >25 mm Hg the A wave increased by 18 +/- 13 cm/s. The change in the E/A ratio during Valsalva correlated fairly with LVEDP (r = -0.72, SEE 8.8 mm Hg), the baseline E/A ratio correlated poorly, and scatter was substantial (r = 0.46, SEE 11.2 mm Hg). Just as elevated filling pressures can mask impaired relaxation, the impaired relaxation pattern can mask the presence of elevated filling pressures. This can be revealed by testing the response of the A wave to the Valsalva maneuver, allowing estimation of LVEDP independent of the baseline E/A ratio.

Relation between lesion characteristics and risk with percutaneous intervention in the stent and glycoprotein IIb/IIIa era: An analysis of results from 10,907 lesions and proposal for new classification scheme.

BACKGROUND: The currently used American College of Cardiology/American Heart Association lesion classification scheme dates from an era when balloon angioplasty was the only percutaneous treatment available and major complications occurred in approximately 7% of patients. Major advances in treatment options would suggest that this scheme may be outmoded, but the schemes that have been suggested to update lesion classification have not been widely accepted. METHODS AND RESULTS: Four thousand one hundred eighty-one consecutive patients (6,676 lesions) formed a training set and 2,146 patients (4,231 lesions) formed a validation set treated from 1995 to 1997 at a single center used by 3 hospital groups. Twenty-seven pretreatment candidate variables were analyzed with the use of stepwise proportional logistic regression, and 9 (nonchronic total occlusion with TIMI flow 0, degenerated vein graft, vein graft age >10 years, lesion length >/= 10 mm, severe calcium, lesion irregularity, large filling defect, angulated >/= 45 degrees plus calcium, and eccentricity) were independently correlated (P<0.05) with ranked adverse outcome (death, Q-wave or creatine kinase >/= 3x normal myocardial infarction, or emergency coronary artery bypass grafting>>creatine kinase 2 to 3x myocardial infarction>>possibly related to non-Q-wave myocardial infarction>>no complication). A scheme based on these findings and the old American College of Cardiology/American Heart Association scheme were found to have c-statistics in the validation set of 0.672 and 0.620 (P = 0.010 vs old scheme), respectively. CONCLUSIONS: Appreciation of these contemporary risk factors for complications of coronary intervention may assist in patient selection and in risk adjustment for comparison of outcomes between providers.

Development of transplantation vasculopathy and progression of donor-transmitted atherosclerosis: comparison by serial intravascular ultrasound imaging.

BACKGROUND: Transplant coronary artery disease is a combination of atherosclerosis transmitted from the donor and new lesions of allograft vasculopathy. We sought to determine the morphological characteristics of allograft vasculopathy and differentiate it from donor-transmitted atherosclerosis with serial intravascular ultrasound. METHODS AND RESULTS: Intravascular ultrasound examination was performed in 93 patients at 27.2+/-15.0 and 369. 7+/-23.9 days after transplantation. The maximally and minimally diseased sites were selected in each segment as defined by Coronary Artery Surgery Study classification. For each matched site, maximal plaque thickness was measured. Lesions (maximum plaque thickness >/=0.5 mm) present at baseline examination were defined as donor lesions. On follow-up, lesions that developed at previously normal sites were defined as de novo lesions. The distribution and severity of donor and de novo lesions were similar in proximal, mid, and distal segments. The de novo lesions were less focal (43% vs 74%) and more circumferential (69% vs 45%) compared with the donor lesions, but there was significant morphological heterogeneity. Similar numbers of patients with and those without donor lesions developed de novo lesions. Moreover, progression of donor lesions was not associated with the presence or absence of de novo lesions. CONCLUSIONS: Differentiation between early allograft vasculopathy from conventional atherosclerosis by distribution and morphology of lesions alone is difficult. Serial intravascular ultrasound imaging with early baseline examination is necessary to make this distinction. This distinction is important because the progression of donor lesions and the development of de novo lesions are independent of each other.

Clinical experience with abciximab during coronary revascularisation: an overview.

Despite improvements in the safety and efficacy of percutaneous transluminal coronary angioplasty (PTCA), ischaemic procedural complications continue to occur in up to 10 to 20% of patients. As the pivotal role of platelets in the formation of arterial thrombosis following coronary intervention was elucidated, it became apparent that an inhibitor of platelet aggregation might reduce the rate of acute ischaemic complications and restenosis following PTCA. Attention has focused on the platelet glycoprotein (GP) IIb/IIIa integrin, a receptor that mediates the final common pathway of platelet aggregation. A murine monoclonal antibody that binds to and blocks the IIb/IIIa receptor inhibits the binding of fibrinogen to platelets and thus inhibits platelet aggregation. To minimise the potential for human anti-murine antibody responses, this antibody was modified to a chimaeric antibody fragment, abciximab (c7E3 Fab), composed of an antigen-binding fragment with human constant regions and mouse variable regions. Abciximab was recently approved by the US Food and Drug Administration for clinical use. The efficacy and safety of abciximab have been demonstrated in 3 recently completed phase III clinical trials which enrolled a total of 6156 patients undergoing coronary angioplasty. The study results have unequivocally demonstrated that platelet GP IIb/IIIa receptor inhibition with abciximab during coronary intervention markedly reduces the incidence of postprocedural ischaemic events. In the EPIC trial, a dose-related effect of abciximab in the prevention of ischaemic complications was observed, with a significant 35% reduction in the incidence of the composite end-point among the patients receiving the abciximab bolus and 12-hour infusion compared with the double-placebo group. In the EPILOG trial, patients treated with abciximab bolus and 12-hour infusion with low-dose heparin had a significant 56% reduction in the incidence of the composite end-point at 30 days. In the CAPTURE study, the primary end-point was reduced at 30 days by 29% with abciximab therapy. The treatment effect observed at 30 days for reduction in acute ischaemic complication was maintained throughout the 6-month follow-up period. Although abciximab therapy may carry an increased risk of bleeding complications, such excess haemorrhagic risk can be eliminated by strategies such as reduction of adjunctive heparin dosage, early sheath removal, and conservative management of the vascular access site. The role of platelet glycoprotein IIb/IIIa receptor inhibition in the acute coronary syndromes of unstable angina and acute myocardial infarction treated by percutaneous intervention or with thrombolytic therapy is an exciting new frontier in ischaemic heart disease and is currently under investigation. The complementarity of these agents with new devices for coronary revascularisation, such as stents, is also the subject of important new trials. Finally, future studies will also focus on the role of long term GP IIb/IIIa inhibition with the new generation of orally active agents.

The role of nitric oxide in coronary vascular effects of estrogen in postmenopausal women.

BACKGROUND: At physiological concentrations, 17beta-estradiol selectively enhances endothelium-dependent coronary vasodilation by an unknown mechanism in postmenopausal women. METHODS AND RESULTS: To assess the contribution of nitric oxide (NO) to the vascular effects of estradiol, we measured coronary epicardial and microvascular responses to intracoronary acetylcholine (range, 3 to 300 microg/min for 2 minutes) before and after intracoronary estradiol 75 ng/min for 15 minutes in 20 estrogen-deficient women, 16 of whom had angiographic evidence of atherosclerosis or risk factors for atherosclerosis. This testing was repeated after inhibition of NO synthesis with intracoronary N(G)-monomethyl-L-arginine (L-NMMA) 64 micromol/min for 5 minutes. Estradiol increased acetylcholine-stimulated coronary flow from 54+/-48% (mean+/-SD) above baseline values before estradiol infusion to 100+/-63% above baseline values (P=.007) and decreased coronary resistance from 32+/-21% to 46+/-15% below baseline values (P=.007) at a coronary sinus estradiol concentration of 1725+/-705 pmol/L (470+/-192 pg/mL). Estradiol also tended to lessen the severity of acetylcholine-induced epicardial coronary artery vasoconstriction from 8+/-11% to 3+/-11% below baseline values (P=.123). However, during L-NMMA infusion, estradiol no longer potentiated the effects of acetylcholine on coronary flow dynamics; coronary flow increased 39+/-46% above baseline values and coronary resistance decreased 19+/-30% below baseline values (both P<.001 versus pre-L-NMMA responses). The epicardial diameter decreased 8+/-11% below baseline values (P=.06 versus pre-L-NMMA response). CONCLUSIONS: The effects of estradiol at physiological concentrations on endothelium-dependent coronary vasodilator responsiveness in postmenopausal women are mediated by enhanced bioavailability of NO, which may be responsible in part for the cardioprotective effects of estrogen.

Monocytes harboring cytomegalovirus: interactions with endothelial cells, smooth muscle cells, and oxidized low-density lipoprotein. Possible mechanisms for activating virus delivered by monocytes to sites of vascular injury.

Cytomegalovirus (CMV) infection and its periodic reactivation from latency may contribute to atherogenesis and restenosis. It is unknown how CMV is delivered to the vessel wall and is reactivated. We examined the following hypothesis: CMV, present in monocytes recruited to sites of vascular injury, is activated by endothelial cell (EC) or smooth muscle cell (SMC) contact and by oxidized low-density lipoproteins (oxLDLs). The CMV major immediate-early promoter (MIEP) controls immediate-early (IE) gene expression, and thereby viral replication. To determine whether elements of the vessel wall can activate CMV present in monocytes, we transiently transfected the promonocytic cell line HL-60 with a chloramphenicol acetyltransferase reporter gene construct driven by MIEP. MIEP activity increased 1.7 +/- 0.5-fold (P = .02) when the transfected HL-60 cells were cocultured with ECs, 4.5 +/- 1.5-fold when cocultured with SMCs (P = .03), and 2.0 +/- 0.5-fold (P = .01) when exposed to oxLDL. The combination of oxLDL and EC coculture increased MIEP activity over 7-fold. We also found that freshly isolated human monocytes, infected with endothelium-passaged CMV, were capable of transmitting infectious virus to cocultured ECs or SMCs. CMV-related progression of atherosclerosis or restenosis may, at least in part, involve monocyte delivery of the virus to the site of vascular injury, where the vascular milieu, ie, contact with ECs, SMCs, and oxLDL, can contribute to viral reactivation and/or replication by enhancing CMV IE gene expression. The virus may then infect neighboring ECs or SMCs, initiating a cascade of events predisposing to the development of atherogenesis-related processes.

Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women.

BACKGROUND: Plasma levels of plasminogen-activator inhibitor type 1 (PAI-1), an essential inhibitor of fibrinolysis in humans, increase in women after menopause, and this may contribute to the risk of cardiovascular disease. We studied the effects of hormone-replacement therapy on PAI-1 levels. METHODS: In a randomized, crossover study, we investigated the effects of oral conjugated estrogen (0.625 mg per day) in 30 postmenopausal women and transdermal estradiol (0.1 mg per day) in 20 postmenopausal women, either alone or in combination with medroxyprogesterone acetate (2.5 mg daily) for one month, on plasma PAI-1 antigen levels. Degradation products of cross-linked fibrin (D-dimer) were measured in serum as an index of fibrinolysis. RESULTS: PAI-1 levels were inversely associated with D-dimer levels at base line (r= -0.540, P=0.002). Conjugated estrogen, both alone and in combination with medroxyprogesterone acetate, reduced mean (+/-SD) plasma levels of PAI-1 from 32+/-34 ng per milliliter to 14+/-10 ng per milliliter (P<0.001) and from 31+/-29 ng per milliliter to 15+/-11 ng per milliliter (P=0.003), respectively; there was a significant inverse correlation between pretreatment PAI-1 levels and the degree of reduction in these levels during therapy (r= -0.631, P<0.001 for conjugated estrogen; r = -0.507, P=0.004 for combined therapy). The degree of reduction in PAI-1 levels was associated with increases in D-dimer levels both when conjugated estrogen was given alone (r= -0.572, P=0.001) and when combined hormone therapy was given (r= -0.541, P=0.002). Transdermal estradiol caused no significant changes in PAI-1 levels from base-line values. CONCLUSIONS: Conjugated estrogen, alone or combined with progestin therapy, reduced PAI-1 levels by approximately 50 percent in postmenopausal women and was associated with enhanced systemic fibrinolysis. These findings may partly explain the protective effect of hormone-replacement therapy with respect to coronary artery disease.

Effects of the antiestrogen tamoxifen on low-density lipoprotein concentrations and oxidation in postmenopausal women.

Our study demonstrates that tamoxifen, when administered to postmenopausal women at a conventional dosage, reduces LDL levels and protects LDL from oxidation. The protective effect of tamoxifen against the development of breast cancer in women considered at risk is being investigated in a placebo-controlled trial sponsored by the National Institutes of Health. Whether tamoxifen also protects against the development of cardiovascular disease in this trial is also of considerable interest.

Effect of combined 17 beta-estradiol and vitamin E on low-density lipoprotein oxidation in postmenopausal women.

In conclusion, combined administration of 17beta-estradiol and vitamin E protects LDL in postmenopausal women from oxidation with no synergism noted compared with either therapy given alone.

Effect of antioxidant vitamins on low density lipoprotein oxidation and impaired endothelium-dependent vasodilation in patients with hypercholesterolemia.

OBJECTIVES: The aims of this study were to determine whether antioxidant vitamins could reduce the susceptibility of low density lipoprotein (LDL) to oxidation and improve endothelium-dependent vasodilator responsiveness in patients with hypercholesterolemia. BACKGROUND: Animals and humans with hypercholesterolemia have exhibited impaired endothelium-dependent vasodilation. In vitro studies suggest that oxidatively modified LDL can impair nitric oxide production. METHODS: Forearm blood flow was measured with strain gauge plethysmography and brachial artery drug infusions in 19 patients, aged 52 +/- 9 years, with hypercholesterolemia (mean +/- SD total cholesterol 283 +/- 22 mg/dl, LDL 197 +/- 31 mg/dl) and in 14 subjects, aged 48 +/- 8 years, with normal cholesterol levels (total cholesterol 169 +/- 20 mg/dl, LDL 102 +/- 25 mg/dl). Acetylcholine (7.5, 15 and 30 micrograms/min) was utilized as an endothelium-dependent vasodilator, and sodium nitroprusside (0.8, 1.6 and 3.2 micrograms/min) was used to test endothelium-independent vasodilation. Oxidative susceptibility of LDL was measured by a spectrophotometric assay of conjugated diene production after the addition of copper chloride. Hypercholesterolemic patients then received daily antioxidant vitamin supplements (beta-carotene [30 mg], ascorbic acid [vitamin C] [1,000 mg], vitamin E [800 IU]) for 1 month, with repeat measurement of both forearm blood flow responsiveness to the same agonists and LDL oxidizability. RESULTS: The maximal flow in response to acetylcholine was impaired in patients compared with that in normal subjects (9.8 +/- 7.8 vs. 15.9 +/- 8.1 ml/min per 100 ml, p = 0.03), with similar maximal flow responses to sodium nitroprusside (9.5 +/- 4.2 vs. 9.0 +/- 2.8 ml/min per 100 ml, p = 0.72). After 1 month of vitamin therapy, the onset of LDL oxidation was prolonged over baseline measurements by 71 +/- 67%, and the maximal rate of oxidation was decreased by 26 +/- 25% (both p < 0.001). However, the maximal forearm blood flow response to acetylcholine remained unchanged from baseline values (maximal flow after acetylcholine 9.0 +/- 6.2 vs. 9.8 +/- 7.8 ml/min per 100 ml, p = 0.57). This study had 80% power (alpha = 0.05) to exclude a 45% increase over baseline value in acetylcholine-stimulated flow during vitamin therapy. CONCLUSIONS: Although 1 month of administration of antioxidant vitamin supplements in hypercholesterolemic patients reduced the susceptibility of LDL to oxidation, impairment in endothelial function remained unaltered. The use of nonvitamin antioxidants or concomitant reduction in LDL levels, as well as more sensitive techniques for measuring vascular responsiveness, may be required to show a beneficial effect on endothelial vasodilator function.

Selective loss of microvascular endothelial function in human hypercholesterolemia.

BACKGROUND: Endothelial dysfunction is increasingly recognized as an early and important feature of vascular disease. Endothelium-dependent vasodilation is impaired in humans with hypercholesterolemia, although it is unknown whether this defect is selective for some pathways of nitric oxide production or indicates a more generalized abnormality of endothelial function. The aim of this study was to further elucidate the nature of endothelial dysfunction in human hypercholesterolemia by comparing vascular responses of agonists that use different signal transduction pathways to activate production of nitric oxide. METHODS AND RESULTS: Forearm flow was measured in 12 hypercholesterolemic patients (total cholesterol, 286 +/- 35 mg/dL [mean +/- SD]) aged 50 +/- 11 years and in 12 healthy subjects (total cholesterol, 173 +/- 27 mg/dL) aged 48 +/- 7 years using strain-gauge plethysmography and brachial artery drug infusions. The endothelium-dependent vasodilators used were acetylcholine (7.5, 15, and 30 micrograms/min), which uses a pertussis toxin-sensitive signal transduction pathway, and bradykinin (100, 200, and 400 ng/min), which uses a pertussis toxin-insensitive signal transduction pathway to activate nitric oxide production. Sodium nitroprusside (0.8, 1.6, and 3.2 micrograms/min) was used to test endothelium-independent vasodilation. The maximum flow in response to acetylcholine was markedly impaired in patients compared with healthy subjects (8.0 +/- 5.1 versus 17.5 +/- 7.7 mL.min-1. 100 mL-1, P = .002). However, the maximum forearm flow in response to bradykinin was similar in the two groups (13.0 +/- 4.5 versus 16.2 +/- 5.5 mL.min-1 x 100 mL-, P = .14), as was the maximum flow in response to sodium nitroprusside (7.0 +/- 2.8 versus 8.4 +/- 2.2 mL.min-1 x 100 mL-1, P = .13). NG-Monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, reduced the maximum forearm vasodilation induced by bradykinin to the same extent in patients and in healthy subjects (-29 +/- 8% versus -32 +/- 6% reduction in peak flow, P = .80), with similar maximum flows in response to bradykinin (9.2 +/- 4.0 versus 10.4 +/- 2.6 mL.min-1 x 100 mL-1, P = .35). CONCLUSIONS: Hypercholesterolemic patients are capable of normal nitric oxide bioavailability in response to bradykinin. Impairment of microvascular endothelial vasodilator function in human hypercholesterolemia is selective, and the defect occurs at the level of the acetylcholine receptor or its signal transduction pathway.

First derivative of right ventricular pressure, dP/dt, as a sensor for a rate adaptive VVI pacemaker: initial experience.

Ten patients underwent implantation of a rate adaptive ventricular pacing system with a new pulse generator and lead. The unipolar lead has a steroid eluting tip and a pressure sensor. The first derivative of the signal from this sensor, dP/dt, is determined and the pacemaker rate is varied in response to changes in the right ventricular dP/dtMAX. During implantation, dP/dt values were in the range of 180-720 mm Hg/sec. The autothreshold for pacing at 2.5 V remained unchanged 1 month after implantation (0.065 +/- 0.045 msec, range 0.05-2.00 msec) and only slightly increased after 3 months (0.075 +/- 0.045 msec, range 0.05-2.00 msec). A significant correlation existed between the dP/dt measured during implantation and the right ventricular pressure measured by telemetry at follow-up visits (r = 0.93, P = 0.0001). Initial pacemaker programming was performed on the second day after implantation following a short walk and was adjusted subsequent to follow-up visits according to the patient's subjective assessment and in accordance with the results of exercise tests and Holter monitoring. Exercise and Holter tests did not significantly change initial programming. There was a significant correlation between right ventricular systolic pressure and the rate response setting (r = -0.66, P less than 0.05). During dP/dt pacing, all patients felt well, and eight of these reported an improvement compared to nonrate adaptive pacing. The heart rate response to effort and recovery was appropriate. It was concluded that: (1) right ventricular dP/dt is a suitable parameter for controlling the pacing rate; (2) appropriate programming of the dP/dt pacemaker results in a suitable heart rate response to exercise and recovery.

Transesophageal electrocardiography using a temporary pacing balloon-tipped electrode in acute cardiac care.

STUDY OBJECTIVE: The study was undertaken to determine the feasibility of obtaining esophageal ECGs using resterilized 3F temporary pacing balloon-inflated electrodes in place of the more expensive pill-electrode and its associated expensive preamplifier. SETTING: Tests were conducted in the emergency department and ICU. TYPE OF PARTICIPANTS: Subjects were 12 acutely ill patients for whom standard 12-lead surface ECGs were insufficient to afford accurate, immediate arrhythmia diagnosis. INTERVENTIONS: Reasonable quality esophageal ECGs were obtained by use of the electrodes, generally with minimal patient discomfort. The test never required more than ten minutes. Of the 12 patients who participated in this preliminary study, esophageal ECGs enabled definitive diagnoses to be made in ten cases. CONCLUSION: The use of resterilized temporary pacing balloon-inflated electrodes enables esophageal ECGs to be obtained in an acute care setting.

Abnormalities in bilirubin and liver enzyme levels in adult patients with bacteremia. A prospective study.

Eighty-four patients with bacteremia were surveyed prospectively for biochemical markers of liver damage. Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin levels were elevated in 44 (53%), 39 (47%), 45 (54%), and 5 (6%) of the patients on the first determination (2.0 +/- 0.1 days after onset of fever) and in 11 (13%), 17 (20%), 26 (31%), and 1 (1%) on the second determination (5.4 +/- 0.2 days after onset of fever), respectively. The elevation rarely exceeded three times the upper limit of normal. One patient had severe jaundice. An abnormality of at least one of these values was found in 55 patients (65%). There were no differences in site of infection, bacteria isolated, and outcome between patients with and without biochemical abnormalities. We conclude that in adult patients with bacteremia, elevation of liver enzymes and bilirubin is common, usually mild, of short duration, and of no prognostic significance.