Green coffee polyphenols do not attenuate features of the metabolic syndrome and improve endothelial function in mice fed a high fat diet.

We have investigated the effects of the major polyphenol in coffee, chlorogenic acid (CGA), on obesity, glucose intolerance, insulin resistance, systemic oxidative stress and endothelial dysfunction in a mouse model of the metabolic syndrome. Thirty C57BL6 mice were randomly divided into (n=10/group) (i) normal diet (ND), (ii) high fat diet (HFD), or (iii) high fat diet supplemented with 0.5% w/w green coffee bean extract (GCE) rich in chlorogenic acid (HFD+GCE). The high fat diet consisted of 28% fat and all animals were maintained on their diets for 12 weeks. The mice fed a HFD and HFD+GCE displayed symptoms of the metabolic syndrome compared to their normal fed counterparts, although no endothelial dysfunction was detected in the abdominal aortas after 12 weeks. GCE did not attenuate HFD-induced obesity, glucose intolerance, insulin resistance or systemic oxidative stress. Furthermore, GCE did not protect against ex vivo oxidant (hypochlorous acid)-induced endothelial dysfunction.

Latissimus dorsi tendon transfer for irreparable tears of the rotator cuff: An anatomical study to assess the neurovascular hazards and ways of improving tendon excursion.

Latissimus dorsi tendon transfer (LDTT) is technically challenging. In order to clarify the local structural anatomy, we undertook a morphometric study using six complete cadavers (12 shoulders). Measurements were made from the tendon to the nearby neurovascular structures with the arm in two positions: flexed and internally rotated, and adducted in neutral rotation. The tendon was then transferred and measurements were taken from the edge of the tendon to a reference point on the humeral head in order to assess the effect of a novel two-stage release on the excursion of the tendon. With the shoulder flexed and internally rotated, the mean distances between the superior tendon edge and the radial nerve, brachial artery, axillary nerve and posterior circumflex artery were 30 mm (26 to 34), 28 mm (17 to 39), 21 mm (12 to 28) and 15 mm (10 to 21), respectively. The mean distance between the inferior tendon edge and the radial nerve, brachial artery and profunda brachii artery was 18 mm (8 to 27), 22 mm (15 to 32) and 14 mm (7 to 21), respectively. Moving the arm to a neutral position reduced these distances. A mean of 15 mm (8 to 21) was gained from a standard soft-tissue release, and 32 mm (20 to 45) from an extensile release. These figures help to define further the structural anatomy of this region and the potential for transfer of the latissimus dorsi tendon.

Oxidized low-density lipoprotein downregulates endothelial basic fibroblast growth factor through a pertussis toxin-sensitive G-protein pathway: mediator role of platelet-activating factor-like phospholipids.

BACKGROUND: Oxidized LDL (oxLDL) inhibits angiogenesis in part by downregulating endothelial basic fibroblast growth factor (bFGF). To determine the mechanism of the downregulation, we investigated the signal transduction pathway involving potential phospholipid mediators. METHODS AND RESULTS: Cultured bovine aortic endothelial cells were incubated with PBS (lipoprotein-free control), LDL, or copper oxLDL under serum-free conditions. At 24 hours, oxLDL (50 microg/mL) decreased bFGF mRNA (Northern blot), bFGF protein (Western blot and ELISA), and concomitant DNA synthesis, all by 40% to 50% compared with PBS. LDL had no effect. Pretreating the cells with 100 ng/mL pertussis toxin (PTX) for 18 hours before oxLDL exposure almost completely blocked the inhibitory effects of oxLDL. In contrast, inhibiting other major cellular signal transduction pathways with PD-98059 (mitogen-activated protein kinase kinase inhibitor), HA-1004 (inhibitor of cGMP- and cAMP-dependent protein kinase), or Ro-31-8220 (protein kinase C inhibitor) or chelating intracellular Ca(2+) with BAPTA-AM failed to attenuate any of the oxLDL effects assayed. Addition to the cultures of WEB 2086, a specific antagonist of the PTX-sensitive G protein-coupled platelet-activating factor (PAF) receptor, blocked the action of oxLDL. Whereas PAF dispersed in the culture medium failed to produce oxLDL-like effects, degradation of PAF and PAF-like phospholipids accumulated in oxLDL with a recombinant human PAF acetylhydrolase eliminated the inhibitory effects of oxLDL on bFGF expression and DNA synthesis. CONCLUSIONS: OxLDL suppresses endothelial bFGF expression and DNA synthesis through a PTX-sensitive heterotrimeric G-protein pathway involving mediator phospholipids similar, but not identical, to PAF.

Oxidized low-density lipoproteins inhibit endothelial cell proliferation by suppressing basic fibroblast growth factor expression.

BACKGROUND: Hyperlipidemia inhibits proliferation of endothelial cells (ECs) in culture and angiogenesis in vivo and in arterial explants. Elucidation of the mechanisms may suggest novel therapies against atherosclerosis. METHODS AND RESULTS: Basic fibroblast growth factor (bFGF) expression and mitogenic effects were assessed in bovine aortic ECs incubated with oxidized LDL (ox-LDL). Compared with native LDL and lipoprotein-free controls, ox-LDL reduced bFGF mRNA levels in a time- and concentration-dependent manner, 100 microg/mL producing a maximum reduction of 40% to 50% within 24 to 48 hours. There were commensurate reductions in intracellular and extracellular bFGF concentrations, DNA and total RNA syntheses, and cell replication. FGF receptor 1 and beta-actin mRNA levels were unchanged. Ox-LDL accelerated bFGF mRNA degradation in actinomycin D-treated cells. However, inhibition of bFGF expression by ox-LDL was attenuated by cyclohexamide, indicating a requirement for continuous new protein synthesis for posttranscriptional destabilization. Reduced syntheses of DNA and total RNA were completely restored by bFGF but not by vascular endothelial growth factor. Inhibition of total RNA synthesis achieved by exposing cells to a bFGF-neutralizing antibody was similar in magnitude to that induced by ox-LDL. CONCLUSIONS: Cytotoxic effects of ox-LDL on ECs are attributable in part to suppression of bFGF expression.

Shocks as predictors of survival in patients with implantable cardioverter-defibrillators.

OBJECTIVES: The objective of the study was to determine whether the occurrence of shocks for ventricular tachyarrhythmias during therapy with implantable cardioverter-defibrillators (ICD) is predictive of shortened survival. BACKGROUND: Ventricular tachyarrhythmias eliciting shocks are often associated with depressed ventricular function, making assessment of shocks as an independent risk factor difficult. METHODS: Consecutive patients (n = 421) with a mean follow-up of 756+/-523 days were classified into those who had received no shock (n = 262) or either one of two shock types, defined as single (n = 111) or multiple shocks (n = 48) per arrhythmia episode. Endpoints were all-cause and cardiac deaths. A survival analysis using a stepwise proportional hazards model evaluated the influence of two primary variables, shock type and left ventricular ejection fraction (LVEF <35% or >35%). Covariates analyzed were age, gender, NYHA Class, coronary artery disease, myocardial infarction, coronary revascularization, defibrillation threshold and tachyarrhythmia inducibility. RESULTS: The most complete model retained LVEF (p = 0.005) and age (p = 0.023) for the comparison of any shock versus no shock (p = 0.031). The occurrence of any versus no shock, or of multiple versus single shocks significantly decreased survival at four years, and these differences persisted after adjustment for LVEF. In the LVEF subgroups <35% and <25%, occurrence of multiple versus no shock more than doubled the risk of death. Compared with the most favorable group LVEF > or =35% and no shock, risk in the group multiple shocks and LVEF <35% was increased 16-fold. CONCLUSIONS: In defibrillator recipients, shocks act as potent predictors of survival independent of several other risk factors, particularly ejection fraction.

Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group.

BACKGROUND: Patients with implantable cardioverter-defibrillators often receive adjunctive antiarrhythmic therapy to prevent frequent shocks. We tested the efficacy and safety of sotalol, a beta-blocker with class III antiarrhythmic effects, for this purpose. METHODS: In a multicenter trial, patients were stratified according to left ventricular ejection fraction (< or =0.30 or >0.30), randomly assigned to double-blind treatment with 160 to 320 mg of sotalol per day (151 patients) or matching placebo (151 patients), and followed for 12 months. Kaplan-Meier analyses of the time to an event were performed. Three end points were used: the delivery of a first shock for any reason or death from any cause, the first appropriate shock for a ventricular arrhythmia or death from any cause, and the first inappropriate shock for a supraventricular arrhythmia or death from any cause. RESULTS: Compliance with double-blind treatment was similar in the two groups. There were seven deaths in the placebo group and four in the sotalol group. As compared with placebo, treatment with sotalol was associated with a lower risk of death from any cause or the delivery of a first shock for any reason (reduction in risk, 48 percent; P<0.001 by the log-rank test), death from any cause or the delivery of a first appropriate shock (reduction in risk, 44 percent; P=0.007), or death from any cause or the delivery of a first inappropriate shock (reduction in risk, 64 percent; P=0.004). Sotalol also reduced the mean (+/-SD) frequency of shocks due to any cause (1.43+/-3.53 shocks per year, as compared with 3.89+/-10.65 in the placebo group; P=0.008). In the sotalol group, the reduction in the risk of death from any cause or the delivery of a first shock for any reason did not differ significantly between patients with ejection fractions of more than 0.30 and those with ejection fractions of 0.30 or less. CONCLUSIONS: Oral sotalol was safe and efficacious in reducing the risk of death or the delivery of a first defibrillator shock whether or not ventricular function was depressed.

Comparison of results in two implantable defibrillators. Jewel 7219D Investigators.

The Jewel 7219D was the first non-thoracotomy implantable cardioverter-defibrillator (ICD) with biphasic shock capability small enough to be placed in the prepectoral subcutaneous position. Size reduction of ICDs is desirable, but safety and efficacy of smaller devices must be demonstrated. Outcomes of patients treated with the Jewel 7219D defibrillator (n = 1,781) and with its precursor model PCD 7217B (n = 2,637) were compared. To use PCD patients (n = 2,637) as historical (n = 2,574) and concurrent controls (n = 63), statistical adjustments using the Cox proportional-hazards regression model were made. Jewel recipients (n = 1,781) treated in 106 US and 32 non-US centers exhibited similar characteristics including a mean age of 59 years, 78% men, ejection fraction of 34%, history of aborted sudden cardiac death in 41%, and coronary artery disease in 70%. Implantation was completed in 1,777 of 1,781 (99.9%) attempts and success with the first electrode configuration and polarity was 89.5%. Kaplan-Meier cumulative first-year survivals for cardiac and all-cause mortality were 98.5% and 93.3%. Complication-free first-year survival for Jewel implants in prepectoral subcutaneous (n = 582), subpectoral submuscular (n = 366), and abdominal (n = 449) positions did not differ (p > 0.05). First-year survival free of pocket-related complications exceeded 98% in all locations. Adjusted cardiac and all-cause first-year mortality, and efficacy in terminating spontaneous tachyarrhythmias did not differ between the 2 device groups. In conclusion, the safety and efficacy of Jewel model 7219D in the prepectoral subcutaneous position are at least equal to either those of Jewel models implanted in different positions or to those of the previously extensively characterized PCD 7217B.

Impaired adaptive vascular growth in hypercholesterolemic rabbit.

Occlusive arterial disease stimulates compensatory growth of pre-existent and new arterial channels which help to maintain organ perfusion. Previous studies characterizing compensatory or collateral vascular growth have been performed in normocholesterolemic animals. Because hyperlipidemic states alter vascular regulation, it remains to be demonstrated that the capacity of the vasculature to undergo compensatory growth is preserved in the presence of dyslipidemic vascular injury. To assess effects of hypercholesterolemia on vascular growth, arterial supply to the ear of rabbits with (n = 13) or without hypercholesterolemia (n = 14) was surgically restricted. Compensatory growth of residual arteries and distal microvessels was evaluated using quantitative angiographic and microanatomic methods. Lumen-expanding hyperplasic arterial remodeling and distal microvascular proliferation induced by arterial restriction were assessed by independent techniques including in vivo microangiography, laser Doppler flowmetry, quantitative histometry, and thymidine incorporation. Compared with controls, hypercholesterolemic rabbits exhibited depressions in all arterial and capillary growth indexes. Microvascular proliferation in hypercholesterolemic rabbits was less than 20% of control. Results demonstrate for the first time that an atherogenic dyslipidemia may limit compensatory macro- and microvascular growth in response to arterial restriction, a phenomenon that could play an important role in the pathophysiology of atherosclerotic occlusive artery disease.

Altering molecular mechanisms to prevent sudden arrhythmic death.

Trials of drug treatment for prevention of sudden arrhythmic death have been disappointing, perhaps because suppressive therapy with arrhythmic agents fails to address the mechanisms leading to electrophysiological failure. We propose that preventive treatment should pay more attention to molecular mechanisms responsible for the progression of cardiac disease to electrophysiological failure. Most sudden cardiac deaths occur in people with atherogenic dyslipidaemias. Our hypothesis is that the pathogenic molecular mechanisms of dyslipidaemias contribute directly to arrhythmogenesis. Proinflammatory-prothrombotic lipid-derived mediators that may play a part in arrhythmogenesis include phospholipids and leucotrienes acting through the platelet-activating-factor and peroxisome proliferator-activated-receptor pathways. There are drugs available to test the hypothesis of dyslipidaemias-specific prevention of electrophysiological failure.

Conscious sedation with combined hypnotic agents for implantation of implantable cardioverter-defibrillators.

OBJECTIVES: The objective of this study was to evaluate the feasibility, safety and efficacy of placing implantable cardioverter-defibrillators (ICDs) in the electrophysiology laboratory using conscious sedation with combined hypnotic agents and deep sedation with etomidate. BACKGROUND: Implantable cardioverter-defibrillators with transvenous leads permit the use of simplified implantation techniques similar to those used for the insertion of permanent pacemakers. However, implantation of ICDs without general anesthesia has thus far gained limited acceptance. METHODS: In 162 patients, conscious sedation during ICD placement was achieved with combined intravenous midazolam, morphine and promethazine (Phenergan). Intravenous etomidate was administered to induce deep sedation for defibrillation threshold testing. First-time implantations were in the prepectoral position (n = 142), but some patients with preexisting devices received abdominal implants (n = 20). The results were compared with those of concurrent patients (n = 56) who received prepectoral implants under propofol anesthesia administered by an attending anesthesiologist. RESULTS: The anesthetic protocol was implemented without major intraoperative complications. During deep sedation with etomidate, episodes of apnea, hypoxia or arterial hypotension requiring therapeutic intervention did not occur. During a mean (+/-SD) follow-up period of 257 +/- 140 days (median 227, range 14 to 482), there were, among the 162 patients, a total of two nonsudden cardiac deaths-one 71 days and the other 157 days after the operation. There were two nonsudden deaths in the concurrent control subjects (n = 56)-one 13 days and the other 110 days after the operation. CONCLUSIONS: Implantation of ICDs under conscious sedation with combined hypnotic agents and deep sedation with etomidate is a safe and effective procedure with low perioperative morbidity and low long-term complication rates.

Atherosclerosis as a microvascular disease: impaired angiogenesis mediated by suppressed basic fibroblast growth factor expression.

We present evidence that hypercholesterolemia and oxidized low-density lipoprotein (ox-LDL) impair endothelial cell growth by suppressing basic fibroblast growth factor (bFGF) expression. Background studies show that diet-induced hypercholesterolemia in rabbits impairs hyperplastic lumen-expanding remodeling of the carotid artery in response to a chronic flow load. Hypercholesterolemia also markedly impairs compensatory macrovascular and microvascular growth in rabbit ears with surgical restriction of arterial supply. In an in vitro model of angiogenesis, arterial explants cultured in a three-dimensional collagen gel exhibited organized endothelial cell growth with formation of capillary-like microtubes (CLM). CLM growth was sensitive to inhibition by neutralizing antibodies against bFGF. With explants excised from both the aorta of hypercholesterolemic rabbits and from coronary arteries of patients with coronary arteriosclerosis, CLM growth and release of immunoassayable bFGF to the culture medium were suppressed. Growth suppression was reversed partially by exogenous bFGF. In control explants, ox-LDL produced a suppression of CLM growth that could be reversed by exogenous bFGF. In endothelial cells in culture, ox-LDL suppressed bFGF expression and DNA synthesis in a dose-dependent manner. We conclude that atherosclerosis is associated with impaired bFGF-dependent endothelial cell growth manifested by impaired adaptive growth responses of large arteries and microvessels.

Inhibitory effects of hypercholesterolemia and ox-LDL on angiogenesis-like endothelial growth in rabbit aortic explants. Essential role of basic fibroblast growth factor.

Hypercholesterolemic (HC) rabbits exhibit suppressed compensatory vascular growth after restriction of arterial supply. However, neovascularization is commonly found in atheromas containing inflammatory cells. We used an in vitro model to determine the effects of hypercholesterolemia on angiogenesis in the absence or presence of inflammatory cells. HC rabbit aortic explants (1 mm2) with or without (n = 90 each) lesion-forming inflammatory cells were cultured in a collagen matrix with serum-free medium. Explant-derived endothelial cell growth was organized into capillary-like microtubes (CLM) that could be videomicroscopically quantified. CLM growth from lesion-free HC explants was significantly reduced to 13 +/- 4% of the value in explants (n = 90) from normocholesterolemic (NC, n = 15) rabbits (P < .001). In contrast, in lesion-containing HC explants, the matrix was invaded by foam cells, and CLM growth was not inhibited. Immunoassayable basic fibroblast growth factor (bFGF, in pg/mL) in the culture medium was significantly lower in lesion-free HC (< 5) than NC explants (11 +/- 2, P < .01) or HC explants with lesions (14 +/- 3). In addition, CLM growth was reduced in NC explants incubated with oxidized LDL (ox-LDL, 50-100 micrograms/mL). Exogenous bFGF (10 ng/mL) reversed the inhibitory effects of hypercholesterolemia and ox-LDL, whereas bFGF-neutralizing antibody (10 micrograms/mL) abolished CLM growth in all groups. In cultured rabbit aortic endothelial cells, ox-LDL reduced DNA synthesis, but this inhibition was reversed by bFGF. We conclude that hypercholesterolemia and ox-LDL inhibit angiogenesis like endothelial growth because of a suppressed availability of endogenous bFGF. Retained responsiveness to exogenous bFGF suggests that inducing bFGF expression at targeted sites may improve collateral growth in hyperlipidemic arterial disease.

Effect of preexisting epicardial patch electrodes on defibrillation thresholds of unipolar defibrillators.

The question is addressed whether patients with thoracotomy defibrillators and failing epicardial electrodes can be effectively treated with the implantation of prepectoral unipolar ("active can") defibrillators. Results indicate that abandoned epicardial patches in the pathway of unipolar defibrillation currents do not affect defibrillation thresholds and active can efficacy.

Spontaneous ventricular tachycardia treated by antitachycardia pacing. Cadence Investigators.

The database of the registry for an implantable cardioverter defibrillator was analyzed to determine the efficacy and safety of antitachycardia pacing for the termination of ventricular tachycardia. In 22,339 episodes treated, termination occurred in 94% and acceleration in only 1.4%.

Long-term follow-up of cardioverter-defibrillator implanted under conscious sedation in prepectoral subfascial position.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) with intravenous electrode systems and downsized generators can be implanted by use of operative techniques similar to those employed for the insertion of permanent pacemakers. However, the safety, efficacy, and long-term follow-up of simplified implantation procedures remain to be evaluated. This report is a prospective long-term evaluation of nonselected patients receiving ICDs in the prepectoral subfascial position under conscious sedation. METHODS AND RESULTS: Clinical characteristics of the 231 consecutive patients included a mean age of 63 years, a male-to-female ratio of 6.4, a left ventricular ejection fraction of 0.34, a mild-to-moderate heart failure in 91%, coronary artery disease in 84%, and a history of aborted sudden cardiac death or refractory ventricular tachyarrhythmias. Insertion of transvenous leads and prepectoral subfascial ICD implantation were performed in electrophysiology laboratories under local anesthesia and conscious sedation with intravenous midazolam and propofol. Successful implantation in all patients (operation time, 80 +/- 32 minutes, mean +/- SD) irrespective of body size and skin thickness was free of major complications, including need for emergency intubation. After surgery, 1 pocket hematoma, 1 seroma, and 1 pneumothorax required treatment. There was no operative or first-month mortality. During long-term follow-up averaging 453 +/- 296 days, six leads required repositioning, but pocket erosions or infections did not occur. First-year total survival was 97%. CONCLUSIONS: Implantation under conscious sedation of ICDs in the prepectoral subfascial position is a safe and effective procedure with low operative and postoperative morbidity and favorable long-term outcome.

Sudden cardiac death: still more questions than answers.

Sudden cardiac death is the leading cause of death in industrialized countries. It is most frequently due to ventricular tachyarrhythmias occurring in the presence of coronary heart disease, but mechanisms linking sudden death to coronary atherosclerosis are still unclear. In autopsy studies of sudden death patients, the incidence of acute thrombotic coronary occlusions has varied between 4 and 74%. In over 600 consecutive patients with implantable cardioverter-defibrillators, we observed that appropriate shocks for electrogram-verified ventricular tachyarrhythmias was only very rarely followed by signs of acute myocardial infarction (< 3% of cases), not supporting the coronary occlusion theory of fatal arrhythmias. Cellular hypertrophy compensating for cell loss due to ischemia, intraventricular hypertension, cardiomyopathy, and myocarditis might play a role in arrhythmogenesis as evidenced by the fact that experimental induction and regression of hypertrophy are paralleled by changes in the inducibility of ventricular tachyarrhythmias. Atherogenic hyperlipidemias are associated with a systemic inflammatory response manifested by leukocytosis (lymphocytosis) and complex upregulations of proinflammatory-prothrombotic mediators, such as platelet-activating factor, cytokines, and hemostasis factors. The diurnal regulation of these mediators parallels circadian rhythms of coronary morbidity and mortality. Some upregulated mediators have been shown to exert direct arrhythmogenic effects. The potential contribution of hyperlipidemia-associated inflammatory factors to arrhythmogenesis is important, because it opens new molecular targets for antiarrhythmic drug design.

Basic fibroblast growth factor reverses atherosclerotic impairment of human coronary angiogenesis-like responses in vitro.

The influence of atherosclerosis on vascular growth in humans was evaluated in an in vitro model of angiogenesis. Coronary artery intima-media explants from patients (n = 10) with coronary artery disease (CAD) (in all cases Stary type V lesions) and patients without CAD (n = 10) were cultured in a collagen matrix containing serum-free medium. Endothelial cell growth from explants was organized as capillary-like microtubes (CLM); the sum of their lengths was morphometrically quantitated as an index of angiogenesis. CLM growth was suppressed in CAD explants (n = 120), the index values at two weeks averaging only 20% +/- 3% of non-CAD explants (n = 120, P < 0.001). Addition of exogenous basic fibroblast growth factor (bFGF) (10 ng/ml) stimulated CLM growth substantially more in the CAD than in the non-CAD group, whereas bFGF-neutralizing antibodies nearly abolished growth in both. Endothelial cells isolated from non-CAD coronary arteries exhibited in culture typical endothelial characteristics, including cobblestone appearance, staining for von Willebrand factor, CLM formation on Matrigel substrate, and sensitivity to bFGF and to bFGF-neutralizing antibody. Inhibition of cell replication by oxidized low-density lipoprotein (OxLDL) was reversed by bFGF. We conclude that human atherosclerosis is associated with impairment of angiogenesis-like endothelial growth and that decreased bFGF availability contributes to the impairment.

Hypercholesterolemia and endothelial dysfunction.

Endothelial cells respond to hemodynamic forces with the expression of different phenotypes with disparate functional properties. At arterial bends and flow dividers, cells are relatively deprived of fluid-shear-stress-induced cell differentiation and exhibit phenotypes with increased mitotic rate, decreased intercellular contact, increased permeability for macromolecules, and the expression of molecules favoring constriction, adhesion, and thrombosis. Arterial sites covered by such cells are vulnerable to the atherogenic effects of hypercholesterolemia. A hallmark of endothelial cells exposed to hypercholesterolemia is a reduced capacity to release endothelium-derived relaxing factor. Pharmacological interventions that suppress or stimulate nitric oxide production appear to enhance or reduce the atherogenic effects of hypercholesterolemia.

Vasoprotection and antihypertensive therapy.

Vasoprotective drugs decrease the vulnerability of blood vessels to cardiovascular risk factors such as hypertension and hypercholesterolemia. Mechanistic treatment end-points of hypertension (normalization of endovascular pressure) may not correct nonhypertensive components of the pathobiology of hypertension. Estrogen replacement therapy, antihypertensive treatment with angiotensin-converting enzyme inhibitors, and manipulations of nitric oxide metabolism may have beneficial effects on vessels in the absence of blood pressure normalization. Estrogens and L-arginine, the precursor of nitric oxide, can partly correct impaired endothelium-dependent vasodilation, a pathophysiologic hallmark of hypertensive states. Angiotensin-converting enzyme inhibitors preserve endothelium-dependent vasodilation and protect arteries against the atherogenic effects of hypercholesterolemia by a non-hypolipidemic, non-hypotensive mechanism.

Hyperlipidemic endothelial injury and angiogenesis.

Hypercholesterolemia is associated with endothelial cell dysfunction which may in part be related to an accumulation of toxic lipoprotein degradation products in artery walls. Oxidized low-density lipoprotein (LDL) and its products have been incriminated in impairing various endothelial functions including G-protein-dependent transmembrane signaling, calcium regulation, phosphoinositide turnover, protein kinase C activation and others. Modification of such cell regulatory functions may alter the responsiveness of endothelial cells to angiogenic (mitogenic) stimuli. Endothelial cell replication is necessary for the growth of preexisting arterial channels and the formation of new microvessels (angiogenesis). Experiments in intact rabbits indicate that endothelial replication necessary for vascular growth is markedly impaired in the presence of hypercholesterolemia, a defect that could play an important role in the pathophysiology of occlusive atherosclerotic disease.