SBP, DBP, and pulse blood pressure variability are temporally associated with the increase in pulse wave velocity in a model of aortic stiffness.

Background: Enhanced aortic stiffness and blood pressure variability (BPV) are independent risk factors for cardiovascular disease and all-cause mortality in man. They are also correlated with increased blood pressure (BP) and/or arterial remodeling. However, the interplay between BP and BPV on the stiffening process is still unclear.

Deamidated lipocalin-2 induces endothelial dysfunction and hypertension in dietary obese mice.

Background: Lipocalin-2 is a proinflammatory adipokine upregulated in obese humans and animals. A pathogenic role of lipocalin-2 in hypertension has been suggested. Mice lacking lipocalin-2 are protected from dietary obesity-induced cardiovascular dysfunctions.

New biologically active hydrogen sulfide donors.

Generous donors: The dithioperoxyanhydrides (CH3 COS)2 , (PhCOS)2 , CH3 COSSCO2 Me and PhCOSSCO2 Me act as thiol-activated hydrogen sulfide donors in aqueous buffer solution. The most efficient donor (CH3 COS)2 can induce a biological response in cells, and advantageously replace hydrogen sulfide in ex vivo vascular studies.

Cardiac FKBP12.6 overexpression protects against triggered ventricular tachycardia in pressure overloaded mouse hearts.

Alterations in RyR2 function have been proposed as a major pathophysiological mechanism of arrhythmias and heart failure (HF). Cardiac FKBP12.6 overexpression protects against myocardial infarction-induced HF and catecholamine-promoted ventricular arrhythmias.

Development and validation of an enzyme-linked immunosorbent assay for the quantification of a specific MMP-9 mediated degradation fragment of type III collagen--A novel biomarker of atherosclerotic plaque remodeling.

Objective: Degradation of collagen in the arterial wall by matrix metalloproteinases is the hallmark of atherosclerosis. We have developed an ELISA for the quantification of type III collagen degradation mediated by MMP-9 in urine.

Design And Methods: A monoclonal antibody targeting a specific MMP-9 generated fragment of collagen III was used in a competitive ELISA.

Innovation in coronary artery disease and heart failure: clinical benefits of pure heart rate reduction with ivabradine.

The link between elevated heart rate and cardiovascular events is established in healthy individuals and in patients with cardiovascular disease. The new agent, ivabradine, specifically and selectively inhibits the I(f) current, with the sole action of heart rate reduction, with no impact on any other cardiac parameters. The benefits of "pure" heart rate reduction with ivabradine have been the focus of one of the largest clinical development programs ever performed, involving >20,000 individuals.

I(f) inhibition in cardiovascular diseases.

Heart rate (HR) is determined by the pacemaker activity of cells from the sinoatrial node (SAN), located in the right atria. Spontaneous electrical activity of SAN cells results from a diastolic depolarization (DD). Despite controversy in the exact contribution of funny current (I(f)) in pacemaking, it is a major contributor of DD.

Effect of uncoupling endothelial nitric oxide synthase on calcium homeostasis in aged porcine endothelial cells.

Aims: The requirement of endothelial NO synthase (NOS3) calcium to produce NO is well described, although the effect of NO on intracellular calcium levels [Ca(2+)](i) is still confusing. Therefore, NO and [Ca(2+)](i) cross-talk were studied in parallel in endothelial cells possessing a functional or a dysfunctional NO pathway.

Methods And Results: Dysfunctional porcine endothelial cells were obtained either in vitro by successive passages or in vivo from regenerated endothelium 1 month after coronary angioplasty.

Status of the endothelium-derived hyperpolarizing factor pathway in coronary arteries after heterotopic heart transplantation.

Background: After the first year of transplantation, the major limitation to long-term survival is the development of graft coronary vasculopathy, characterized by a pathologic activation of the endothelium with an attendant loss of its regulatory properties on homeostasis of the vascular wall. The present study was designed to evaluate the integrity of coronary vascular relaxations attributed to the endothelium-derived hyperpolarizing factor (EDHF) and to study hyperpolarization of smooth muscle cells after heterotopic heart transplantation.

Methods: Six weeks after heart transplantation in a porcine model, vascular reactivity studies of control, native and allograft epicardial coronary artery rings were performed in standard organ chamber experiments.

Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity.

Background And Purpose: Ivabradine, a specific and use-dependent I(f) inhibitor, exerts anti-ischaemic activity purely by reducing heart rate. The aim of this work was to characterize its effect on the predominant HCN channel isoform expressed in human sino-atrial nodes (hSAN), to determine its kinetics in HCN channels from multicellular preparations and rate-dependency of its action.

Experimental Approach: RT-PCR analysis of the four HCN channel isoforms was carried out on RNAs from hSAN.

The discovery of the selective I(f) current inhibitor ivabradine. A new therapeutic approach to ischemic heart disease.

Coronary artery disease is still a major cause of morbidity and mortality in the industrialized countries, despite the advances in pharmacological treatments, risk factor control and the beneficial effect of myocardial revascularization procedures. Medical anti-ischemic treatment is still essential in most patients, but should be improved in terms of efficacy and tolerance to ensure better prevention of mortality and improvement of the quality of life and symptom control. Since increased heart rate plays a major role in coronary artery disease, not only as a trigger of most of the ischemic episodes but also as an independent predictor of mortality, inhibition of the pacemaker I(f) current to induce a direct and selective decrease in heart rate represents an attractive therapeutic approach for coronary artery disease.

[The discovery of the selective If current inhibitor ivabradine (Procoralan): a new therapeutic approach to ischemic heart disease].

Coronary artery disease is still a major cause of morbidity and mortality in the industrialized countries and its prevalence is predicted to grow with the current aging of the population in these countries. In spite of the rapid pace of progress and increasing use of myocardial revascularization procedures, in particular percutaneous coronary interventions, the medical treatment of coronary artery disease has lost none of its relevance in the majority of patients, though conventional drugs have their limitations and the pharmacological approach to ischemic heart disease needs to be improved in terms of efficacy and tolerance to ensure better prevention of mortality and improvement in quality of life. Since increased heart rate plays a major role in coronary artery disease, not only as a trigger of most ischemic episodes, but also as an independent predictor of mortality, inhibition of the pacemaker If current in view of inducing a direct and selective decrease in heart rate represents an ideal conceptual target and an attractive therapeutic approach to coronary artery disease.

Thromboxane A2/prostaglandin H2 receptor activation mediates angiotensin II-induced postischemic neovascularization.

Objective: We analyzed the involvement of thromboxane (TX) A2/prostaglandin (PG) H2 (TP) receptor in ischemia-induced neovascularization in mice.

Methods And Results: Unilateral hindlimb ischemia was induced by right femoral artery ligature in male C57BL/6J mice (n=7 per group). Animals were then treated with or without TP receptor antagonist (S18886, 5 or 10 mg/kg per day; ramatroban, 10 mg/kg per day) or aspirin (30 mg/kg per day) in drinking water for 21 days.

Chronic mild hyperhomocysteinemia induces aortic endothelial dysfunction but does not elevate arterial pressure in rats.

Mild hyperhomocysteinemia is prevalent in the general population and has been linked to endothelial dysfunction and high arterial pressure (AP) in clinical studies. The present study was designed to determine whether a rise in AP was induced by mild hyperhomocysteinemia and whether the potential rise in AP is secondary or prior to endothelial dysfunction. Experiments were performed in a rat model of mild hyperhomocysteinemia induced by oral administration of homocysteine for 1-4 months.

[Selection and pharmacological characterisation of Procoralan, a selective inhibitor of the pacemaker If current].

The screening of a series of benzocycloalkane derivatives led to the selection of Procoralan (ivabradine), the first selective inhibitor of the depolarizing If (funny) current of the sinus node, for the treament of myocardial ischaemia. In vitro, this compound reduces the spontaneous beating rate of isolated right rat atria and the firing rate of the action potential of rabbit sinus node preparations. This effect is explained by a reduction in the diastolic depolarisation slope of the action potential and underlies a selective inhibition of the pacemaker If current.

Role of force--frequency relation during AV-block, sinus node block and beta-adrenoceptor block in conscious animals.

Objective: Myocardial contractility is regulated by adrenergic stimulation, the strength-length relationship and the force-frequency relationship or Bowditch effect. The latter mechanism was clearly demonstrated in muscle strips, in the isolated heart as well as in in-vivo experiments. The aim of this study was to further investigate the role of the force-frequency effect on the contractile response to exercise or isoproterenol infusion in conditions of restricted increases in heart rate i.

Anti-ischemic effects of ivabradine, a selective heart rate-reducing agent, in exercise-induced myocardial ischemia in pigs.

The effects of ivabradine, a novel heart rate-reducing agent that inhibits the cardiac pacemaker current If, were compared with those of the beta-adrenergic blocker propranolol, in a model of exercise-induced regional myocardial ischemia in pigs. Five Yucatan micropigs were chronically instrumented to measure hemodynamics, regional myocardial contractility, and local electrograms, and a fixed stenosis of the left anterior descending coronary artery was induced using a clip. Each animal underwent three experiments on different days, each consisting of two treadmill exercise sessions, 4 hours apart.

Cells derived from regenerated endothelium of the porcine coronary artery contain more oxidized forms of apolipoprotein-B-100 without a modification in the uptake of oxidized LDL.

Increased accumulation of lipoproteins and cholesterol within cells from regenerated endothelium may be responsible for their reported dysfunction. This study compared the presence and uptake of oxidized forms of low-density lipoprotein (LDL) in cells derived from native and regenerated endothelium. Four weeks after balloon denudation, primary cultures of native and regenerated endothelial cells were prepared from porcine coronary arteries.

Persistence of the nitric oxide pathway in the aorta of hypercholesterolemic apolipoprotein-E-deficient mice.

The markers of the bioavailability of NO (endothelium-dependent relaxation to acetylcholine and cyclic GMP content) in the thoracic aorta of apolipoprotein-E-deficient (ApoE KO) mice, 20 weeks old with enriched cholesterol diet or 35 weeks old on regular chow, are not decreased, in contrast with other models of atherosclerosis. However, severe hypercholesterolemia, the presence of atherosclerotic lesions and increased NADPH oxidase activity have been reported as early as at 20 weeks of age. The present experiments were designed to test if an increased capacity of NO production in these mice explains this paradox.

Inhibiting the NO pathway with intracoronary L-NAME infusion increases endothelial dysfunction and intimal hyperplasia after heart transplantation.

Background: The endothelium protects the vascular wall through the nitric oxide (NO) release. Coronary endothelial dysfunction occurs early after heart transplantation and predicts the development of intimal thickening typical of graft coronary vasculopathy.

Objective: We designed this study to examine the effect of endothelial NO synthase (eNOS) inhibition on the endothelial dysfunction caused by rejection and on the development of accelerated atherosclerosis after heart transplantation.

[Dysfunction of the nitric oxide pathway during coronary endothelium regeneration].

Experiments were designed to determine whether or not aging per se or cellular density affects endothelial NO-synthase (eNOS) activity in cultured coronary endothelial cells of the pig. A diminished activity could explain the reduced endothelium-dependent relaxation to bradykinin previously observed during regeneration after endothelial injury. The results demonstrate that cell cultures derived from eight-day old regenerated endothelium exhibit a normal basal production of cyclic GMP, but a reduced response to bradykinin or the Ca2+ ionophore A23187.

Comparison of coronary endothelial dysfunction in the working and nonworking graft in porcine heterotopic heart transplantation.

Background: The nonworking heterotopic heart transplantation model has been used extensively for the study of rejection and coronary endothelial function in different species. The effect of left ventricular loading in a working heart transplantation model, which may be associated with different coronary flow patterns and local nitric oxide release, on the development of coronary endothelial dysfunction and intimal hyperplasia, is unknown.

Methods: Porcine retroperitoneal "nonworking" heterotopic transplantations (n=10) and "working" heart (with left ventricular filling) transplantations (n=7) were performed.

Consequences of reduced production of NO on vascular reactivity of porcine coronary arteries after angioplasty: importance of EDHF.

1 The consequences of the reduced production of nitric oxide (NO) by cells from regenerated endothelium were investigated by measuring membrane potential of smooth muscle cells (SMCs), isometric tension and cyclic nucleotides content in porcine coronary arteries with intimal thickening, four weeks following angioplasty. 2 Under basal conditions, SMCs of coronary arteries with regenerated endothelium were depolarized by 10 mV. This depolarization was associated with 82% decreased level of cGMP without alteration in cAMP.

Surgical experience with retroperitoneal heterotopic heart transplantation in the large white domestic swine.

Accelerated coronary atherosclerosis following heart transplantation is the main limiting factor for long-term survival, aside from graft failure and complications due to immunosuppression. Graft coronary vasculopathy is due to chronic rejection of the vascular wall leading to intimal hyperplasia in coronary arteries. Numerous heterotopic heart transplantation models have been used in different species to study the immunology and pathophysiology following graft implantation.