Endothelin-1 is a key mediator of coronary vasoconstriction in patients with transplant coronary arteriosclerosis.

BACKGROUND: Transplant coronary arteriosclerosis (TCA) is the principal long-term complication in cardiac transplant recipients. The mediators responsible for vascular proliferation and vasoconstriction typical of TCA remain largely unknown. We tested whether endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, contributes to the pathogenesis and manifestations of TCA. METHODS AND RESULTS: BQ-123, an ET-1 receptor-A antagonist, was infused into a coronary artery (40 nmol/min for 60 minutes) of 18 subjects, 6 + or - 4 years after transplantation. Vasomotor responses were measured in the infused artery and in a noninfused control artery in patients with (n=10) and without (n=8) advanced TCA (108 total coronary segments). Changes in diameters were compared at 15-minute intervals up to 60 minutes. Contribution of ET-1 to coronary constrictor tone was assessed by comparing vasodilation from BQ-123 with that of the maximal vasodilator nitroglycerin (200-microg intracoronary bolus). BQ-123 dilated coronary arteries of transplanted patients (8.4% at 60 minutes versus -0.4% in noninfused arteries, P<0.001). Dilation was greater for arteries with advanced TCA defined as diameter stenosis > or = 15% (dilation 15.2% with versus 0.6% without advanced TCA, P=0.004). Judged against the response to nitroglycerin, ET-1 accounted for 53.2% of coronary tone in advanced TCA but only 12.9% without advanced TCA. CONCLUSIONS: This study shows for the first time in humans that ET-1 is an important mediator of coronary vasoconstriction in TCA and accounts for >50% of the increased vasomotor tone. Therapeutic targeting of ET-1 may retard the development of TCA.

Comparison of effects of rosuvastatin (10 mg) versus atorvastatin (40 mg) on rho kinase activity in caucasian men with a previous atherosclerotic event.

In addition to inhibiting cholesterol biosynthesis, statins also inhibit the formation of isoprenoid intermediates, which are required for the activation of the Rho/Rho kinase (ROCK) pathway. Increased ROCK activity has been implicated in causing endothelial dysfunction and atherosclerosis. However, it is not known whether statins, at doses used to lower cholesterol levels, inhibit ROCK activity in humans with atherosclerosis. Furthermore, it is not known whether lipophilic and hydrophilic statins differ in their ability to inhibit ROCK activity. Accordingly, we enrolled 30 men with stable atherosclerosis (low-density lipoprotein [LDL] > or =100 mg/dL) in a randomized, double-blind study comparing equivalent LDL-lowering doses of a hydrophilic statin (rosuvastatin 10 mg once a day) with a lipophilic statin (atorvastatin 40 mg once a day) for 28 days. We assessed the change in lipids, ROCK activity, and flow-mediated dilation (FMD) of the brachial artery before and after statin therapy. Both treatment groups exhibited comparable 30% to 32% and 42% to 45% reductions in total and LDL cholesterol, respectively. Only atorvastatin reduced triglycerides, and neither statin altered high-density lipoprotein cholesterol. Whereas both statins inhibited ROCK activity (p <0.0001), the extent of inhibition was greater with rosuvastatin (18 +/- 2% vs 8 +/- 2%, p = 0.0006). Statins also improved FMD from 7.4 +/- 0.6 to 9.3 +/- 0.4 (p = 0.003) with rosuvastatin being slightly better than atorvastatin. The inhibition of ROCK activity by statins did not correlate with reductions in LDL (p = 0.57) but was associated with improvement in FMD. In conclusion, these findings provide direct clinical evidence that statins, at clinically relevant doses, could differentially inhibit ROCK activity and improve endothelial function by cholesterol-independent mechanism.

Statins inhibit Rho kinase activity in patients with atherosclerosis.

BACKGROUND: In addition to inhibiting cholesterol synthesis, statins (HMG-CoA reductase inhibitors) decrease the formation of isoprenoid intermediates required for the activation of key signaling pathways, including Rho/Rho kinase (ROCK). In experimental settings, statins inhibit ROCK and reverse vascular dysfunctions in atherosclerosis, independent of cholesterol reduction. It is not known whether statins inhibit ROCK activity in humans with atherosclerosis. METHODS: We investigated 35 patients with stable atherosclerosis in a randomized, double-blind study comparing treatment with high-dose (80mg/d) or low-dose (10mg/d) atorvastatin to placebo for 28 days. Blood samples for leukocyte ROCK activity, fasting lipids, and high-sensitivity C-reactive protein (hs-CRP) were obtained on days 0, 7, 14, and 28 after randomization and change over time with the two statin treatments relative to placebo was examined. RESULTS: Atorvastatin 80mg/d reduced ROCK activity (p=0.002 vs. placebo). This decline was rapid and significant within 2 weeks of treatment. The inhibition of ROCK by atorvastatin (80mg/d) remained significant even after controlling for changes in low-density lipoprotein cholesterol (LDL-C) and triglycerides (p=0.01). Furthermore, there was no correlation between changes in ROCK activity and changes in LDL-C (r=0.2, p=0.25) or triglycerides (r=0.1, p=0.55). There was a modest correlation between ROCK inhibition and change in hs-CRP among patients randomized to atorvastatin 80mg/d (r=0.6, p=0.07). CONCLUSIONS: These first-in-man findings demonstrate that high-dose atorvastatin rapidly inhibits the pro-atherogenic Rho/ROCK pathway, independent of cholesterol reduction. This inhibition may contribute to the clinical benefits of statins. Rho/ROCK may provide a useful therapeutic target in patients with atherosclerosis.

Transcoronary ethanol ventricular tachycardia ablation in the modern electrophysiology era.

BACKGROUND: Radiofrequency catheter ablation for ventricular tachycardia (VT) may be unsuccessful when critical portions of the circuit cannot be interrupted with either endocardial or epicardial radiofrequency application. OBJECTIVE: We sought to investigate whether transcoronary ethanol ablation (TCEA) can be used as a therapy for patients with VT who have failed medications and radiofrequency ablation in the modern era. METHODS: Nine patients (7 men, 55 +/- 9 years old, left ventricular ejection fraction 23% +/- 8%, 2.2 +/- 0.8 failed VT ablations) with at least 1 unsuccessful attempt at radiofrequency catheter ablation for symptomatic VT at our institution between 2000 and May 2007 underwent TCEA. The majority of patients had an ischemic cardiomyopathy (67%), and all patients had VT due to scar-related reentry. In the 7 patients with VT involving a septal scar, a septal perforator artery was a suitable target in 5 patients, whereas in the remaining patients, a distal branch of the circumflex and the conus branch of the right coronary artery were targeted. In the 2 patients in whom VT involved an inferior scar, a branch of the posterior descending artery was targeted. RESULTS: Acute success was obtained in 56% of patients (89% for clinical targeted VT). During a mean follow-up of 29 +/- 23 months, 3 deaths occurred and 67% of the patients were free of recurrence. CONCLUSION: TCEA may represent an option in patients with refractory VT in whom radiofrequency ablation fails, especially in cases of septal scar in which failure is thought to be caused by inability to provide adequate lesion depth.

Improved characterization of atherosclerotic plaques by gadolinium contrast during intravascular magnetic resonance imaging of human arteries.

OBJECTIVES: To determine whether gadolinium-DTPA (Gd-DTPA) facilitates discrimination of fibrous, lipid or calcified constituents during intravascular magnetic resonance imaging (IVMRI) of human atherosclerotic arteries. BACKGROUND: Atherosclerotic plaques that cause fatal thrombosis due to rupture have high content of lipid relative to fibrous tissue. We recently demonstrated that IVMRI identifies lipid, fibrous, and calcified components within atherosclerotic human arteries with favorable sensitivity and specificity. Gd-DTPA, a T1-shortening agent, selectively amplifies the signal from fibrous tissue on T1 weighted (T1w) surface MRI. METHODS: A 0.030 in. diameter receiver coil coupled to a 1.5T MR scanner was positioned in iliac arteries of nine subjects with atherosclerosis. Previously validated multi-parametric analysis of T1w and moderate T2w images identified 137 fibrous, lipid and calcified regions of interest within 37 arterial segments. T1w imaging was repeated following 0.1 mmol/kg IV Gd-DTPA infusion. RESULTS: Computer-derived mean gray value in fibrous regions increased by 34.2% with Gd-DTPA (95% CI 24.3-43.5%, p=0.0001) while lipid and calcified regions showed only a non-significant increase of 4.3% (95% CI -0.6 to 9.2%, p=0.0825) and 3.8% (95% CI -1.1 to 7.7%, p=0.103), respectively. The increase in mean gray value with Gd-DTPA was greater for fibrous than for lipid or calcified regions (p=0.0001). CONCLUSIONS: Gd-DTPA selectively enhances signal intensity of fibrous constituents during IVMRI of human atherosclerotic arteries and thus identifies key tissue characteristics associated with plaque stability. These findings have important implications for the assessment of plaque-stabilizing therapies and ultimately for reducing cardiovascular events.

Weight reduction and cardiovascular and metabolic disease prevention: clinical trial update.

In children and adults, weight gain is accompanied by the early and more aggressive manifestations of well-recognized risk factors for atherosclerotic cardiovascular disease (CVD). Because insulin resistance and the later development of type 2 diabetes mellitus also accompany weight gain, the term cardiometabolic risk is now commonly used to describe this emerging global health problem. Weight loss will improve cardiometabolic risk. However, less is known about the effect of weight loss on the development of disease and, most importantly, type 2 diabetes and CVD outcomes in the form of death, myocardial infarction, and stroke. This review describes current clinical research that uses health-promoting lifestyle interventions, new drugs, and even surgery, which are all aimed at weight loss, reduction in disease manifestations, and improved outcomes. These anticipated data are essential for the future development of effective CVD prevention strategies. Results are awaited with great interest.

Antiatherosclerotic effects of statins: LDL versus non-LDL effects.

Cardiovascular risk factors, particularly low-density lipoproteins (LDL), give rise to atherosclerosis and its complications by triggering a dysfunctional endothelium, inflammation, and a procoagulant vascular surface. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibition by statins leads to a fall in circulating and plaque LDL concentrations and improvement in many cellular dysfunctions, but controlled trials only show partial benefit with regard to myocardial infarction, stroke, and cardiovascular death. Emerging clinical evidence now shows that these risk factors also stimulate the activation (isoprenylation) of small G-binding proteins and, through their effectors (Rho-associated kinase) they can activate many or most of the subcellular and vessel wall pathophysiology of atherosclerosis. Inhibition of Rho-kinase can improve these dysfunctions with no changes in LDL. Similarly, statins can diminish the activation of these small G-binding proteins and their downstream effectors in atherosclerosis. This review compares and contrasts the effects of statins on atherosclerosis that are related to changes in LDL with those effects occurring through these alternate lipid pathways, and suggests that the therapeutic control of these small G-binding proteins and their downstream effectors may significantly add to the partial benefits of using statins in patients with atherosclerotic heart disease.

Impact of coronary endothelial function on the progression of cardiac transplant-associated arteriosclerosis: effect of anti-oxidant vitamins C and E.

BACKGROUND: Excessive vascular oxidant stress has been implicated in cardiac transplant-associated arteriosclerosis (TxAA). In a recent placebo-controlled study of 40 cardiac transplant recipients, vitamin C 500 mg twice a day and vitamin E 400 IU twice a day for 1 year retarded the progression of TxAA, as assessed by intravascular ultrasound (IVUS). Endothelial dysfunction is a key feature of TxAA and reflects oxidant stress. We hypothesized that coronary endothelial dysfunction portends greater TxAA progression and a larger therapeutic response to anti-oxidant vitamins. METHODS: In this pre-specified analysis, the 40 cardiac transplant recipients were categorized according to normal or abnormal coronary endothelial vasomotor function at baseline, as assessed by acetylcholine (10(-8) to 10(-6) mol/liter). The effect of anti-oxidant vitamins within these two groups of patients was assessed by the change in intimal index over 1 year using IVUS. RESULTS: With placebo (n = 21), the increase in intimal index was greater in the presence vs absence of endothelial dysfunction (11 +/- 3% vs 5 +/- 1%, p < 0.05). Among patients with endothelial dysfunction (n = 21), the intimal index increased 11 +/- 3% with placebo, but decreased -1 +/- 2% with vitamins (p = 0.002). Among patients with normal endothelial function (n = 14), the intimal index increased 5 +/- 1% with placebo and 1 +/- 1% with vitamins (p < 0.05). CONCLUSIONS: Endothelial dysfunction indicates rapid TxAA progression, even in the statin era. Although anti-oxidant vitamins reduce disease progression in patients with normal or abnormal endothelial function, the magnitude of benefit is larger in patients with endothelial dysfunction.

Characterization of human atherosclerotic plaques by intravascular magnetic resonance imaging.

BACKGROUND: Development and validation of novel imaging modalities to assess the composition of human atherosclerotic plaques will improve the understanding of atheroma evolution and could facilitate evaluation of therapeutic strategies for plaque modification. Surface MRI can characterize tissue content of carotid but not deeper arteries. This study evaluated the usefulness of intravascular MRI (IVMRI) to discern the composition of human iliac arteries in vivo. METHODS AND RESULTS: Initial studies validated IVMRI against histopathology of human atherosclerotic arteries ex vivo. A 0.030-inch-diameter IVMRI detector coil was advanced into isolated human aortoiliac arteries and coupled to a 1.5-T scanner. Information from combined T1-, moderate T2-, and proton-density-weighted images differentiated lipid, fibrous, and calcified components with favorable sensitivity and specificity and allowed accurate quantification of plaque size. The validated approach was then applied to image iliac arteries of 25 human subjects in vivo, and results were compared with those of intravascular ultrasound (IVUS). IVMRI readily visualized inner and outer plaque boundaries in all arteries, even those with extensive calcification that precluded IVUS interpretation. It also revealed the expected heterogeneity of atherosclerotic plaque content that was noted during ex vivo validation. Again, IVUS did not disclose this heterogeneity. The level of interobserver and intraobserver agreement in the interpretation of plaque composition was high for IVMRI but poor for IVUS. CONCLUSIONS: IVMRI can reliably identify plaque composition and size in arteries deep within the body. Identification of plaque components by IVMRI in vivo has important implications for the understanding and modification of human atherosclerosis.

Effect of intensive lipid lowering, with or without antioxidant vitamins, compared with moderate lipid lowering on myocardial ischemia in patients with stable coronary artery disease: the Vascular Basis for the Treatment of Myocardial Ischemia Study.

BACKGROUND: Lipid lowering with statins prevents adverse cardiac events. Both lipid-lowering and antioxidant therapies may favorably affect vasomotor function and thereby improve ischemia. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial, 300 patients with stable coronary disease, a positive exercise treadmill test, 48-hour ambulatory ECG with > or =1 episode of ischemia, and fasting total cholesterol of 180 to 250 mg/dL were assigned to 1-year treatment with intensive atorvastatin to reduce LDL to <80 mg/dL (n=96), intensive atorvastatin to reduce LDL to <80 mg/dL plus antioxidant vitamins C (1000 mg/d) and E (800 mg/d) (n=101), or diet and low-dose lovastatin, if needed, to reduce LDL to <130 mg/dL (n=103; control group). Ischemia end points, including ambulatory ECG monitoring and exercise treadmill testing, and endothelial assessment using brachial artery flow-mediated dilation were obtained at baseline and at 6 and 12 months. Baseline characteristics were similar in all groups. LDL decreased from approximately 153 mg/dL at baseline in the 2 atorvastatin groups to approximately 83 mg/dL at 12 months (each P<0.0001) and from 147 to 120 mg/dL in the control group (P<0.0001). During ambulatory ECG monitoring, mean number of ischemic episodes per 48 hours decreased 31% to 61% in each group (each P<0.001; P=0.15 across groups), without a change in daily heart rate activity. Mean duration of ischemia for 48 hours decreased 26% to 62% in each group (each P<0.001; P=0.06 across groups). Mean exercise duration to 1-mm ST-segment depression significantly increased in each group, but total exercise duration and mean sum of maximum ST depression were unchanged. Angina frequency decreased in each group. There was no incremental effect of supplemental vitamins C and E on any ischemia outcome. Flow-mediated dilation studies indicated no meaningful changes. CONCLUSIONS: Intensive lipid lowering with atorvastatin to an LDL level of 80 mg/dL, with or without antioxidant vitamins, does not provide any further benefits in ambulatory ischemia, exercise time to onset of ischemia, and angina frequency than moderate lipid lowering with diet and low-dose lovastatin to an LDL level of <120 mg/dL.

Evaluating the cardiovascular effects of the thiazolidinediones and their place in the management of type 2 diabetes in relation to the metabolic syndrome.

BACKGROUND: The aim of this work was to review evidence on the contribution of the metabolic syndrome to diabetes and atherosclerosis, to evaluate the effects of the thiazolidinediones (TZDs) on cardiovascular risk, and to assess the clinical use of TZDs and their associated risks and benefits. METHODS: Participants were a multidisciplinary panel of experts in endocrinology, cardiology, and nephrology. Available studies on hyperglycemia, hyperinsulinemia, beta-cell function, dyslipidemia, obesity, hypertension, inflammation, endothelial dysfunction, and vascular reactivity were reviewed through presentations by the experts. Assessments were made regarding the associations between characteristics of the metabolic syndrome, type 2 diabetes, and cardiovascular disease, along with the place of TZDs in therapy and management of related adverse clinical events. A panel was convened in November 2002 to develop conclusions based on scientific evidence presented during the meeting. Summary statements were evaluated based on strength and clinical relevance of the data and approved by all panel members. RESULTS AND CONCLUSIONS: Many characteristics of the metabolic syndrome are present before diabetes develops that greatly contribute to the cardiovascular disease burden associated with the progression of diabetes, such as atherosclerosis and coronary artery disease. Insulin resistance is a fundamental component of the metabolic syndrome, and interventions to improve insulin sensitivity are associated with positive cardiovascular effects. From current experimental and clinical data, TZDs appear to reduce risk factors for future cardiovascular events in patients with type 2 diabetes. Study data up to 2 years have demonstrated that TZDs effectively maintain glycemic control in patients with type 2 diabetes, which is attributed to their insulin-sensitizing effects and preservation of beta-cell function. Potential adverse events of TZDs include weight gain and edema, which are generally manageable. Aside from improving insulin sensitivity, TZDs improve lipid profiles, favorably alter deposition of adipose tissue to the periphery rather than visceral areas, decrease markers of inflammation and endothelial dysfunction, and restore vascular reactivity. These pleiotropic effects have the potential to improve cardiovascular outcomes in patients with type 2 diabetes. Trials are underway to confirm this potentially beneficial addition to proven therapies for hypertension, dyslipidemia, and atherosclerosis.

Vascular basis for the treatment of myocardial ischemia study: trial design and baseline characteristics.

BACKGROUND: Increased low-density lipoprotein (LDL) and oxidized LDL cholesterol levels adversely affect endothelial function in patients with stable coronary artery disease (CAD). Statin drugs are efficacious in primary and secondary prevention of clinical CAD events, but they have not been extensively studied as a treatment for ischemia during routine daily activities or during exercise, indicators of high-risk in patients with stable CAD. The purpose of the Vascular Basis for the Treatment of Myocardial Ischemia study is to determine whether aggressive lowering of LDL cholesterol level with atorvastatin, with or without supplemental antioxidant vitamins C and E, can improve endothelial function and ischemia during ambulatory electrocardiogram (AECG) monitoring and exercise treadmill testing (ETT). METHODS: Patients are eligible when they have ischemia during an ETT and AECG monitoring and when their fasting total cholesterol level is < or =250 mg/dL. Eligible patients are randomized to receive 1 of 3 treatments: intensive atorvastatin to reduce LDL cholesterol level to < or =80 mg/dL, intensive atorvastatin to reduce LDL cholesterol level to < or =80 mg/dL plus antioxidant vitamins C and E, and control of diet and low-dose lovastatin, when needed, to reduce LDL cholesterol level < or = to 130 mg/dL. Patients undergo endothelial function testing, 48-hour AECG monitoring, and ETT at randomization and at 6 and 12 months. RESULTS: A total of 300 patients have been randomized: 101 to receive atorvastatin alone, 103 to receive atorvastatin plus antioxidant vitamins, and 96 to receive placebo. Baseline characteristics are similar across treatment groups. CONCLUSIONS: The Vascular Basis study will provide important insight on the effects of aggressive management of dyslipidemia with statin drugs and antioxidant vitamins in patients with stable but high-risk CAD.

Increased Th1 activity in patients with coronary artery disease.

BACKGROUND: Atherosclerotic lesions are mainly composed of macrophages and T lymphocytes. Specific T helper type 1 (Th1) cytokines and interferon gamma (IFN-gamma) inducible chemokines have been shown to be present in these lesions, modulating the local immunologic response. To explore whether this increase in Th1 activity could also be detected in circulating cells indicating a systemic activation, we studied the peripheral expression of Th1 cytokines and chemokines in patients with coronary artery disease and controls. METHODS AND RESULTS: Fifty patients with coronary artery disease (25 with unstable angina and 25 with stable angina) and 10 controls were studied. Serum interleukin (IL)-12 and IFN-gamma and the expression of IFN-gamma inducible chemokines IP-10, Mig and their receptor CXCR3 in peripheral cells were analyzed. Serum IL-12 and intracellular expression of IFN-gamma were significantly elevated in patients with unstable angina. An enhanced expression of IFN-gamma chemokines IP-10, Mig and CXCR3 in patients with stable angina was also observed. CONCLUSIONS: This study demonstrates an increased systemic inflammatory activity in patients with coronary heart disease with a predominant Th1 response, particularly in patients with unstable angina, suggesting an important role played by this polarization in plaque formation and rupture.

Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.

OBJECTIVES: The purpose of this study was to evaluate the occurrence, locations, and relationship of ventricular tachycardia (VT) to low-voltage areas in dilated cardiomyopathy (DCM). BACKGROUND: The substrate causing monomorphic VT after infarction is characterized by regions of low-voltage (<1.5 mV) scar on electroanatomic maps. The substrate causing VT associated with DCM is less well defined. METHODS: A total of 28 patients were studied with endocardial (26 patients) and epicardial (8 patients) electroanatomic mapping. The VT circuits were defined by entrainment or pace mapping. RESULTS: Ventricular tachycardia was due to focal VT in 5, bundle-branch re-entry in 2, and myocardial re-entry in 22 patients (both focal and re-entry VTs in 1 patient). All patients with myocardial re-entry had endocardial (20 of 20 patients) and/or epicardial (7 of 7 patients mapped) scar. Most (63%) endocardial scars were adjacent to a valve annulus. Of the 19 VT circuit isthmuses identified, 12 were associated with an endocardial scar and 7 with an epicardial scar. All myocardial re-entrant VTs were abolished in 12 of 22 patients, and inducible VT was modified in 4 patients. During follow-up of 334 +/- 280 days, 54% of patients with myocardial re-entry were free of VT despite frequent episodes before ablation. CONCLUSIONS: The VTs in DCM are most commonly the result of myocardial re-entry associated with scar. Scars are often adjacent to a valve annulus, deep in the endocardium, and can be greater in extent on the epicardium than on the endocardium. The use of epicardial mapping and radiofrequency is likely to improve success.

Long-term effect of combined vitamins E and C on coronary and peripheral endothelial function.

OBJECTIVES: We tested whether long-term administration of antioxidant vitamins C and E improves coronary and brachial artery endothelial function in patients with coronary artery disease (CAD). BACKGROUND: Endothelial function is a sensitive indicator of vascular health. Oxidant stress and oxidized low-density lipoprotein (LDL) impair endothelial function by reducing nitric oxide bioavailability in the artery wall. METHODS: We randomly assigned 30 subjects with CAD to combined vitamin E (800 IU per day) and C (1000 mg per day) or to placebos in a double-blind trial. Coronary artery endothelial function was measured as the change in coronary artery diameter to acetylcholine infusions (n = 18 patients), and brachial artery endothelial function was assessed by flow-mediated dilation (n = 25 patients) at baseline and six months. Plasma markers of oxidant stress (oxidized LDL and autoantibodies) were also measured. RESULTS: Plasma alpha-tocopherol (p < 0.001) and ascorbic acid (p < 0.02) increased with active therapy. Compared to placebo, there was no improvement in coronary and brachial endothelial vasomotor function over six months. Although vitamins C and E tended to reduce F2-isoprostanes (p = 0.065), they failed to alter oxidized LDL or autoantibodies to oxidized LDL. CONCLUSIONS: Long-term oral vitamins C and E do not improve key mechanisms in the biology of atherosclerosis or endothelial dysfunction, or reduce LDL oxidation in vivo.

Endothelial function, inflammation, and prognosis in cardiovascular disease.

The vascular endothelium is an active, dynamic tissue that controls many important functions, including regulation of vascular tone and maintenance of blood circulation, fluidity, coagulation, and inflammatory responses. Cardiovascular risk factors affect many of the normal functions of the endothelium. In particular, oxidized low-density lipoprotein cholesterol initiates a series of events that begin with cell activation, endothelial dysfunction, local inflammation, and a procoagulant vascular surface. These conspire to result in plaque formation and ultimately plaque rupture and cardiovascular events. Endothelial dysfunction may be evaluated by means of invasive techniques, such as coronary artery reactivity to acetylcholine, or noninvasive techniques, such as brachial artery ultrasonography. Loss of endothelium-dependent vasodilation is a characteristic feature throughout the development of atherosclerosis, and it is independently related to future adverse cardiovascular risk. Therefore, measurement of endothelial function can possibly be used to determine risk, to triage management, and to improve outcomes. At the same time, inflammation is a crucial factor in the atherosclerotic disease process. To identify and monitor the ongoing inflammatory process, markers of inflammation such as C-reactive protein (CRP) have been studied. Scientific evidence shows that elevated plasma CRP values add to the predictive ability of other established risk factors; moreover, elevated values appear to augment the Framingham Coronary Risk Score in identifying individuals who should be considered for cardioprotective treatment programs. Interestingly, thiazolidinediones (TZDs), peroxisome proliferator-activated receptor-gamma agonists that are effective in the treatment of type 2 diabetes mellitus, not only increase insulin sensitivity but can benefit endothelial function because they exhibit anti-inflammatory effects. For many individuals, including those with the metabolic syndrome and/or type 2 diabetes, endothelial dysfunction and elevated plasma CRP levels indicate increased risk of cardiovascular disease. Notably, the TZDs have been shown to reduce CRP levels and may improve endothelial function.

Prothrombotic and antithrombotic pathways in acute coronary syndromes.

The acute coronary syndromes arise from procoagulant changes in complex plaques, which trigger both platelet activation and coagulation pathways. These 2 pathways intersect at a number of points that form positive-feedback loops to sustain and accelerate thrombus formation. In normal hemostasis and with a healthy endothelium, intravascular thrombosis is prevented, and vascular patency is protected by the fibrinolytic system and a number of antithrombotic factors, such as antithrombin, thrombomodulin, and tissue factor pathway inhibitor. However, atherosclerosis is characterized by a hypercoagulable state, and the fibrinolytic balance is skewed toward occlusive thrombus formation at critical sites on vulnerable plaques. This review focuses on cellular and humoral mechanisms and the antithrombotic strategies that are important during the acute phase of an ischemic coronary syndrome, both in patients managed conservatively and in patients scheduled for an interventional procedure. These strategies include fibrinolytic therapy, antiplatelet therapies (aspirin, clopidogrel, glycoprotein IIb/IIIa receptor inhibitors), and low-molecular-weight heparin.

Effects of statins on inflammation in patients with acute and chronic coronary syndromes.

Inflammation plays a crucial role in the cell biology of atherosclerosis. Coronary risk factors, and particularly low-density lipoprotein (LDL) cholesterol, injure the endothelium and decrease the bioavailability of nitric oxide to promote the expression of proinflammatory genes, cellular adhesion molecules, cytokines, chemokines, and growth factors. For example, the expression of CD40/CD40 ligand increases cell-mediated immune responses to activate a number of inflammatory cells and destabilize atherosclerosis. As part of this response, soluble markers of inflammation that are released into the blood offer insights into the cell biology of inflammation in atherosclerosis. In groups of patients, these markers have provided a means to study inflammatory mechanisms and have supported the value of many of our interventions that prevent cardiovascular disease. Statins have potent effects to reduce LDL cholesterol in the plasma and the artery wall and also appear to have a number of nonlipid effects that decrease inflammatory stimuli. Because statins also reduce some soluble markers of inflammation, it is likely that at least part of their benefit reflects a reduction in vascular inflammation in stable and unstable coronary syndromes. Although these inflammatory markers are valuable tools for studying the mechanisms of atherosclerosis, their use in clinical practice to stratify cardiovascular risk or assess treatment in individual patients requires further evaluation.

Circulating autoantibodies to oxidized LDL correlate with impaired coronary endothelial function after cardiac transplantation.

OBJECTIVE: The oxidative modification of low density lipoprotein (LDL) may play a role in the pathogenesis of transplant-associated arteriosclerosis. Oxidized LDL (OxLDL) is immunogenic as well as atherogenic, and the level of autoantibodies to OxLDL has been taken as an index of the oxidant state of LDL. Because endothelial dysfunction is key in the initiation of transplant-associated arteriosclerosis, we postulated that the level of OxLDL autoantibody is associated with the degree of impairment of coronary endothelial function. METHODS AND RESULTS: Coronary endothelium-dependent dilation was assessed by using intracoronary acetylcholine and endothelium-independent dilation by nitroglycerin in 36 cardiac transplant recipients within 1 year of transplantation. The coronary responses to acetylcholine ranged from -37% (vasoconstriction) to 31% (vasodilation), and the responses to nitroglycerin ranged from 0% to 42% (vasodilation). The coronary vasomotor response to acetylcholine was significantly and inversely related to OxLDL autoantibody levels (r=-0.43, P<0.01) but not LDL levels (r=-0.04, P=0.83) or circulating OxLDL levels detected by monoclonal antibody EO6 (r=-0.27, P=0.11). The coronary artery response to nitroglycerin was not related to levels of OxLDL autoantibodies, LDL, or EO6 (all P=NS). CONCLUSIONS: Autoantibodies to OxLDL are increased in patients with coronary endothelial dysfunction in the first year after cardiac transplantation. The oxidative modification of LDL by inducing endothelial dysfunction in cardiac transplant recipients may be a critical step in the atherogenic effects of LDL and may provide a potential target for therapy.