Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia.

INTRODUCTION: While elevated plasma HDL levels are inversely correlated with cardiovascular events, raising HDL with the CETP inhibitor torcetrapib, however, was associated with increased cardiovascular morbidity and mortality in the ILLUMINATE trial. Whether the deleterious clinical effects of torcetrapib represent a molecule specific off-target effect, a class effect of CETP inhibitors or both is matter of ongoing debate. As such, the aim of the present study was to investigate whether CETP-inhibition with JTT-705, a molecule distinctly different from torcetrapib, impacts on vascular function, a well-established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with type II hyperlipidemia. METHODS AND RESULTS: Eighteen patients were randomized to receive JTT-705 600 mg/d or matching placebo for 4 weeks. Flow-mediated dilation (FMD) was measured using ultrasonography of the brachial artery. HDL-C increased by 26% from 1.14 mmol/l to 1.44 mmol/l (p=0.01) in the JTT-705 group, while triglycerides decreased from 2.52 mmol/l to 1.97 mmol/l (p=0.03). CETP- inhibition with JTT-705, however, did not change FMD (3.1+/-0.6% to 3.6+/-0.4%; p=0.48). Interestingly, in a sub group analysis of patients with lower than median HDL-C (<1.19 mmol/l), FMD increased by 41% in patients vs. patients with higher than median HDL-C (>1.19 mmol/l; p=0.01). Markers of vascular inflammation (CRP, ICAM-1, IL-6, TNF alpha), as well as plasma endothelin-1 levels all remained unchanged throughout the study. CONCLUSION: In patients with type II hyperlipidemia, CETP inhibition with JTT-705 increased HDL-C and lowered triglycerides but improved endothelial function in the subgroup of patients with low baseline HDL-C levels only.

Protection of endothelial function: targets for nutritional and pharmacological interventions.

The vascular endothelium synthesizes and releases a spectrum of vasoactive substances and therefore plays a fundamental role in the basal and dynamic regulation of the circulation. Nitric oxide (NO)-originally described as endothelium-derived relaxing factor-is released from endothelial cells in response to shear stress produced by blood flow, and in response to activation of a variety of receptors. After diffusion from endothelial to vascular smooth muscle cells, NO increases intracellular cyclic guanosine-monophosphate concentrations by activation of the enzyme guanylate cyclase leading to relaxation of the smooth muscle cells. NO has also antithrombogenic, antiproliferative, leukocyte-adhesion inhibiting effects, and influences myocardial contractility. Endothelium-derived NO-mediated vascular relaxation is impaired in spontaneously hypertensive animals. NO decomposition by free oxygen radicals is a major mechanism of impaired NO bioavailability. The resulting imbalance of endothelium-derived relaxing and contracting substances disturbs the normal function of the vascular endothelium. Endothelin acts as the natural counterpart to endothelium-derived NO. Besides its arterial blood pressure rising effect in humans, endothelin-1 induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. Current therapeutic strategies concentrate mainly on lowering low-density lipoprotein cholesterol and an impressive reduction in the risk for cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms play an important role in vascular disease and inflammatory plasma markers correlate with prognosis. The production of reactive oxygen species under pathological conditions may represent an important inflammatory trigger. Novel therapeutic strategies specifically targeting inflammation thus bear great potential for the prevention and treatment of atherosclerotic vascular disease. In this context, the vascular actions of flavanol-rich cocoa, particularly with regard to enhanced NO synthesis and endothelial function observed in humans following consumption, warrants further attention. This review discusses pharmacological and dietary intervention.

Cardiovascular disease in HIV infection.

The survival of patients with HIV infection who have access to highly active antiretroviral therapy has dramatically increased. In HIV-infected persons, cardiovascular disease can be associated with HIV infection, opportunistic infections or neoplasias, use of antiretroviral drugs or treatment of opportunistic complications, mode of HIV acquisition (such as intravenous drug use), or with the classic non-HIV-related cardiovascular risk factors (such as smoking or age). Diseases of the heart associated with HIV infection or its opportunistic complications include pericarditis and myocarditis. Pericarditis may lead to pericardial effusion rarely causing tamponade. Cardiomyopathy is often clinically silent with asymptomatic left ventricular systolic dysfunction. Endocarditis is mainly the consequence of intravenous drug abuse, possibly leading to life-threatening valvular insufficiency with the need for cardiac surgery. A further serious condition associated with HIV infection is pulmonary hypertension potentially leading to right heart failure. The cardiovascular complications of HIV infection such as cardiomyopathy and pericarditis have been reduced by highly active antiretroviral therapy, but premature coronary atherosclerosis is now a growing problem because antiretroviral drugs can lead to serious metabolic disturbances resembling those in the metabolic syndrome. Lipodystrophy, a clinical syndrome of peripheral fat wasting, central adiposity, dyslipidemia, and insulin resistance, is most prevalent among patients treated with protease inhibitors. These patients should thus be screened for hyperlipidemia, hyperglycemia, and hypertension, and they may be candidates for lipid-lowering therapies. When initiating lipid-lowering therapy, interactions between statins and HIV protease inhibitors affecting cytochrome P450 function must be considered. Restenosis rate after percutaneous coronary intervention may be unexpectedly high.

Rapid progression of atherosclerotic coronary artery disease in patients with human immunodeficiency virus infection.

We describe the case of a 39-year-old human immunodeficiency virus (HIV)-infected man with angiographically documented rapid progression of coronary artery disease. Over a time course of only 2 months, he developed high-grade stenosis of the left anterior descending coronary artery. The risk of myocardial infarction is increased in patients with HIV infection receiving antiretroviral therapy. However, the absolute risk is small and the marked overall benefits of antiretroviral therapy are evident. Patients receiving HIV protease inhibitors should be screened for hyperlipidemia, hyperglycemia, and hypertension. They may be candidates for lipid-lowering therapies depending on their long-term prognosis and individual risk of cardiovascular disease. Care is need because of possible drug interactions between lipid-lowering drugs and antiretroviral therapy. Invasive treatment of acute myocardial infarction does not differ from that in patients not infected with HIV. The rate of progression of coronary artery disease and the restenosis rate, however, are often unexpectedly high in these patients.

Cardiac arrest in a soccer player: a unique case of anomalous coronary origin detected by 16-row multislice computed tomography coronary angiography.

Anomalous origin of the coronary arteries may be present in otherwise normal subjects without clinical significance, but can also be the cause of myocardial ischemia and sudden death in both adults and teenagers. In particular, the origin of the left main coronary artery or left anterior descending artery from the right sinus of Valsalva or right coronary artery may result in compression of the vessel during or immediately after exercise. We present a unique case of coronary anomaly with four separate coronary ostia originating from the right coronary sinus in a soccer player with sudden cardiac arrest. Multislice contrast-enhanced computed tomography has emerged as a valid noninvasive method for the diagnosis of coronary artery anomaly.

Endogenous estrogens increase postischemic hyperemia in the skin microcirculation.

Estrogens have been recognized as a major regulator of vascular tone and structure, particularly in the skin. The objective of this study was to investigate the effects of endogenous estrogens on the skin microcirculation. Skin blood flow was measured at the forearm at rest and during postischemic hyperemia using laser Doppler flowmetry in 32 healthy women (mean age 34.5 +/- 3.9 years) involved in an in-vitro fertilization program. Women were treated for 10 to 12 days with gonadotropin-releasing hormone agonist (total dose 40.3 +/- 3.3 mg) and human menopausal gonadotropin (1942 +/- 801 IE) or follicle-stimulating hormone (2544 +/- 1071 IE) according to individual estrogen levels. Plasma estrogen levels increased from 132 +/- 90 pmol/L (36 +/- 25 pg/mL) to 8471 +/- 4386 pmol/L (2308 +/- 1195 pg/mL) during treatment (P < 0.0001). Maximal hyperemic blood flow increased from 353 +/- 81% before treatment to 516 +/- 144% after hormonal stimulation (P < 0.0001), whereas basal skin flow was not altered. This study shows that endogenous estrogens enhance the postischemic hyperemic response of the skin microcirculation.

Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension.

Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.

Shear stress-dependent platelet function after LDL cholesterol apheresis.

BACKGROUND: Platelets play a crucial role in the pathogenesis of acute coronary syndrome (ACS). Thrombus formation with subsequent arterial occlusion is a major determinant in ACS and stroke. Platelets also essentially contribute to the development and progression of atherosclerotic lesions. The aim of the present study was to investigate the effects lipid lowering by LDL apheresis on platelet function in patients with coronary artery disease. METHODS: In six patients with angiographically proven coronary artery disease, venous blood samples were obtained before and after LDL cholesterol apheresis. Citrated whole blood (200 microl) was circulated in polystyrene wells at a shear rate of 1875 s(-1) for 2 min with a rotating teflon cone. Shear-stress dependent platelet adhesion was measured before and after apheresis. RESULTS: After apheresis, there were significant reductions in LDL (-58%) and HDL (-17%) cholesterol, triglycerides (-43%), fibrinogen (-52%), lipoprotein (a) (-57%) and CRP (-57%) levels. LDL apheresis significantly reduced shear-stress dependent platelet adhesion. Bolus administration of heparin significantly prolonged activated clotting time, but had no significant effect on platelet adhesion or aggregates. CONCLUSIONS: In patients with coronary artery disease, shear-stress dependent platelet adhesion is reduced by a single LDL apheresis. In addition to its cholesterol-lowering effect, LDL apheresis reduces circulating levels of fibrinogen and C-reactive protein.

Lyme carditis: restitutio ad integrum documented by cardiac magnetic resonance imaging.

Lyme disease is a tickborne illness that could cause, weeks to months later, complications involving the joints, central nervous system, and cardiovascular system. We report a case of cardiac manifestation with transitory higher degree atrioventricular block and dysfunction of the left ventricle. Complete resolution without signs of myocardial scar is demonstrated by cardiac magnetic resonance imaging.

Double aortic and pulmonary valves: An artifact generated by ultrasound refraction.

Echocardiography is an essential diagnostic tool for the investigation of the cardiovascular system. However, the nature of the ultrasound beam may lead to artifacts such as doubling of cardiac structures because of refraction. Here we present two illustrative cases showing doubling of the aortic ring and double regurgitation through the pulmonary valve. Doubling by refraction is different from other artifacts generating double images, such as mirroring of the ultrasound beam (eg, by prosthetic valves). Anatomic structures between the transducer and the heart such as the pleura, pericardium, or rib cartilage may induce refraction of the ultrasound beam resulting in doubling of cardiac structures. The resulting doubling of anatomic structures must not be misdiagnosed.

HDL and inflammation in atherosclerosis.

Atherosclerotic vascular disease is among the most frequent causes of death worldwide. Current therapeutic strategies concentrate mainly on lowering of low-density lipoprotein (LDL) cholesterol and an impressive reduction in the risk for cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms are more and more recognized to play an important role in vascular disease as inflammatory markers correlate with prognosis in acute and chronic coronary artery disease. HDL cholesterol exerts anti-inflammatory effects on the vasculature. Moreover, HDL is an antioxidant, inhibits thrombogenesis, and has pro-fibrinolytic properties. Last but not least, HDL mediates reverse cholesterol transport. These pleiotropic effects make HDL an ideal therapeutic target for novel therapeutic strategies specifically aiming at HDL elevation for the prevention and treatment of atherosclerotic vascular disease.

ETA receptors mediate vasoconstriction of large conduit arteries during reduced flow in humans.

Vascular tone is regulated by endothelium-derived vasodilating and constricting substances, mainly nitric oxide and endothelin (ET)-1. These 2 mediators, which antagonize the actions of each other, are released in response to shear-stress produced by blood flow. The aim of this study was to delineate the contribution of endogenous ET-1 on vascular tone of a large conduit artery during reduced and hyperemic flow. Radial artery diameter was continuously measured with a high-resolution ultrasonic echo-tracking device in 8 healthy subjects. After establishing stable baseline conditions, a wrist cuff was inflated to suprasystolic pressure for 5 minutes. In another 5 subjects, measurements were obtained during intraarterial infusion of saline or an ETA receptor antagonist (BQ-123, 1 nmol/min) in a dosage not affecting basal radial diameter. Wrist occlusion caused a progressive vasoconstriction of the radial artery (P = 0.0001). Vasoconstriction of the radial artery during wrist occlusion was significantly attenuated by ETA receptor antagonism (-2.7% +/- 0.6% versus -6.8% +/- 0.6% during saline, P = 0.007). Flow-mediated vasodilation was not influenced by BQ-123 (7.5% +/- 0.8% versus 7.8% +/- 1.1%, P = NS). This study demonstrates active vasoconstriction of large conduit arteries during conditions of reduced blood flow via ETA receptoractivation. This may play an important role in disease states with reduced systemic or local blood flow and indicates the therapeutic potential of ETA receptor antagonism.

Statins enhance postischemic hyperemia in the skin circulation of hypercholesterolemic patients: a monitoring test of endothelial dysfunction for clinical practice?

OBJECTIVES: The present study aims to investigate whether laser Doppler flowmetry can be used to monitor improvements in vascular function during statin therapy. BACKGROUND: Endothelial dysfunction is an early feature of atherosclerosis in hypercholesterolemic patients and can be improved by statins. There are several methods to assess endothelial function in vivo, none of them being feasible in everyday practice. METHODS: Skin perfusion, measured by laser Doppler flowmetry, was assessed at rest and during reactive hyperemia. Nineteen hypercholesterolemic patients (age 42 to 73 years, total cholesterol 5.4 to 9.6 mmol/l) were studied before and during statin therapy. To further investigate the mechanisms, postischemic skin hyperemia was measured before and after intradermal injection of the nitric oxide synthase inhibitor L-NAME and its inactive isoform D-NAME (0.5 micromol/10 microl each). On a separate day, the healthy volunteers were reexamined before and 2 h after 1,000 mg aspirin. RESULTS: Postischemic skin blood flow was markedly reduced in hypercholesterolemic patients (45 +/- 11%) compared with healthy controls (238 +/- 20%, p < 0.0001) and improved after statin therapy (113 +/- 15%, p = 0.0005 vs. pre-treatment). In the healthy volunteers, the hyperemic responses were not significantly different after L-NAME and D-NAME. Aspirin reduced hyperemia from 274 +/- 49% to 197 +/- 40% (p = 0.025). CONCLUSIONS: Reactive hyperemia of the skin microcirculation can be easily and reproducibly assessed by laser Doppler flowmetry. Vasodilator prostaglandins are the major mediators of postischemic skin hyperemia, which is impaired in hypercholesterolemic patients and can be enhanced by cholesterol-lowering therapy. Thus, laser Doppler flowmetry may represent a tool to assess and monitor vascular function during therapy in everyday practice.

Will endothelin receptor antagonists have a role in heart failure?

Mixed ET(A/B) and selective ET(A) receptor antagonists showed promising hemodynamic and symptomatic improvements in patients with heart failure. Randomized, clinical trials to investigate the effects of ET receptor antagonists on survival in patients with heart failure still need to be conducted. Also, the effects of selective ET(A) and mixed ET(A/B) receptor antagonists on the clinical outcome of patients with CHF will have to be assessed.

Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality. Striking similarities exist in the inflammatory and immunologic response in RA and atherosclerosis. Indeed, adhesion molecules and cytokines, tumor necrosis factor (TNF)-alpha in particular, are key mediators of joint inflammation and of vascular dysfunction and progression of atherosclerotic vascular disease. Hence, the aim of the present study was to assess the effect of chronic antiinflammatory treatment with the anti-TNF-alpha antibody infliximab on disease activity and endothelial function in patients with active RA. METHODS AND RESULTS: Eleven RA patients (mean age 46+/-5 years; disease duration 9+/-2 years) with high disease activity despite treatment with stable doses of methotrexate (