Christian Thuillez

Clinical applications of arterial stiffness, Task Force III: recommendations for user procedures

In vivo arterial stiffness is a dynamic property based on vascular function and structure. It is influenced by confounding factors like blood pressure (BP), age, gender, body mass index, heart rate, and treatment. As a consequence, standardization of the measurement conditions is imperative. General and method/device-specific user procedures are discussed. The subjects conditions should be standardized before starting measurements. These conditions include a minimal resting period of 10 min in a quiet room. It also includes prohibitions on smoking, meals, alcohol, and beverages containing caffeine before measurements. The position of the subject and time of measurements should be standardized. In comparative studies, corrections should be made for confounding factors. Repeated measurements are done preferably by the same investigator, and if available validated with user-independent automated procedures. As it is not feasible to discuss all methods or devices measuring arterial stiffness in one article, more attention is given to user procedures of commercially available devices, because these devices are of interest for a wider group of investigators. User procedures of methods/devices are discussed according to the nature of arterial stiffness measured: systemic, regional, or local arterial stiffness. Each section discusses general or method/device-specific user procedures and is followed by recommendations. Each recommendation discussed during the First International Consensus Conference on the Clinical Applications of Arterial Stiffness is quoted with the level of agreement reached during the conference. Also proposals for future research are made.

Role of Endogenous Endothelin in Chronic Heart Failure Effect of Long-term Treatment With an Endothelin Antagonist on Survival, Hemodynamics, and Cardiac Remodeling

BACKGROUND Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF. METHODS AND RESULTS Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)). Bosentan 100 mg x kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg x kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival. CONCLUSIONS Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.

Long-Term Heart Rate Reduction Induced by the Selective If Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure

Background—Heart rate reduction (HRR) improves left ventricular (LV) filling, increases myocardial O2 supply, and reduces myocardial O2 consumption, which are all beneficial in congestive heart failure (CHF). However, the long-term effects of HRR on cardiac function and remodeling are unknown. Methods and Results—We assessed, in rats with CHF, the effects of long-term HRR induced by the selective If current inhibitor ivabradine (as food admix for 90 days starting 7 days after coronary artery ligation). To assess intrinsic modifications of LV tissue induced by long-term HRR, all parameters were reassessed 3 days after interruption of treatment. Ivabradine decreased heart rate over the 90-day treatment period (−18% versus untreated at 10 mg · kg−1 · d−1), without modifying blood pressure, LV end-diastolic pressure, or dP/dtmax/min. Ivabradine significantly reduced LV end-systolic but not end-diastolic diameter, which resulted in preserved cardiac output due to increased stroke volume. In the Langendorff preparation, ivabradine shifted LV systolic but not end-diastolic pressure-volume relations to the left. Ivabradine decreased LV collagen density and increased LV capillary density without modifying LV weight. Three days after interruption of treatment, the effects of ivabradine on LV geometry, shortening, and stroke volume persisted despite normalization of heart rate. Conclusions—In rats with CHF, long-term HRR induced by the selective If inhibitor ivabradine improves LV function and increases stroke volume, preserving cardiac output despite the HRR. The improvement of cardiac function is related not only to the HRR per se but also to modifications in the extracellular matrix and/or function of myocytes as a consequence of long-term HRR.

Improvement of Endothelial Function by Chronic Angiotensin-Converting Enzyme Inhibition in Heart Failure Role of Nitric Oxide, Prostanoids, Oxidant Stress, and Bradykinin

BACKGROUND-Chronic heart failure (CHF) impairs the endothelium-dependent, flow-mediated dilation (FMD) of small arteries. However, whether chronic angiotensin-converting enzyme (ACE) inhibition affects the impairment of FMD in CHF is unknown. We investigated the effects of long-term ACE inhibition on the FMD of peripheral arteries in rats with CHF and the mechanism(s) involved. METHODS AND RESULTS-FMD was assessed in isolated, perfused gracilis muscle arteries from sham-operated, and untreated or ACE inhibitor-treated (perindopril 2 mg. kg(-1). day(-1) for 10 weeks) rats with CHF (coronary artery ligation). The role of nitric oxide (NO), prostaglandins, and free radicals was assessed by pretreating the vessels with the NO synthase inhibitor N(W)-nitro-L-arginine, the cyclooxygenase inhibitor diclofenac, or the free radical scavenger N-2-mercaptopropionyl-glycine (MPG). Endothelial NO synthase mRNA expression was determined by reverse transcriptase polymerase chain reaction. In animals with hemodynamic and echographic signs of CHF, FMD was converted into vasoconstriction, and this was prevented by ACE inhibition. FMD of arteries from sham-operated or ACE inhibitor-treated CHF rats was abolished by N(W)-nitro-L-arginine. In untreated CHF rats, FMD was increased by diclofenac and MPG. In contrast, in arteries from ACE inhibitor-treated rats, neither diclofenac nor MPG affected FMD. In parallel, ACE inhibition prevented the reduction of endothelial NO synthase mRNA by CHF. CONCLUSIONS-In CHF, ACE inhibition normalized NO-dependent dilatation and suppressed the production of vasoconstrictor prostanoid(s), resulting in improved FMD. The improvement of FMD might contribute to the beneficial effects of ACE inhibition during CHF.

Tissue Doppler Imaging Differentiates Physiological From Pathological Pressure-Overload Left Ventricular Hypertrophy in Rats

Background—The myocardial velocity gradient (MVG) is a recent index of regional myocardial function derived from endocardial and epicardial velocities obtained by tissue Doppler imaging (TDI). This index might be useful for discriminating between physiological and pathological left ventricular hypertrophy (LVH) and for documenting the early transition from compensated LVH to heart failure. We sought to compare MVG measured across the left ventricular posterior wall between normal rats and rats with physiological (exercise) and pathological (pressure-overload) LVH. Methods and Results—Wistar rats were assigned to one of the following groups: sedentary, exercise (swimming), and 2-month or 9-month abdominal aortic banding. Compared with sedentary rats, exercise and 2-month banding led to similar and significant LVH. After 2-month banding, conventional parameters of systolic function (left ventricular fractional shortening and dP/dtmax) were not affected. However, systolic and diastolic MVG were similar in exercise and sedentary rats but were significantly lower in rats with aortic banding. Aortic debanding after 2 months led to a full recovery of MVG, whereas MVG remained decreased when debanding was performed after 9 months. Conclusions—Myocardial contraction and relaxation assessed by TDI were impaired in pressure-overload LVH but not in exercise LVH. Therefore, TDI is more sensitive than conventional echocardiography for assessing myocardial dysfunction in pressure-overload LVH and for predicting early recovery in myocardial function after loading conditions normalization.

Exercise Improves Flow-Mediated Vasodilatation of Skeletal Muscle Arteries in Rats With Chronic Heart Failure Role of Nitric Oxide, Prostanoids, and Oxidant Stress

BACKGROUND Flow-mediated dilatation (FMD) of the peripheral arteries may be impaired in chronic heart failure (CHF), and this could contribute to the increased peripheral resistance and exercise intolerance that occur with this disease. Physical exercise improves the FMD of large conduit arteries in CHF, but whether a similar impairment also occurs in smaller arteries is unknown. The mechanisms of the changes in FMD after CHF or exercise are also unknown. METHODS AND RESULTS FMD was assessed in isolated, perfused, and preconstricted gracilis muscle arteries from sham-operated rats or CHF rats (coronary artery ligation) who were either sedentary or exercised (30-minute swimming period twice a day for 10 weeks, starting 7 days after ligation). In animals with hemodynamic and echographic signs of CHF, FMD was abolished and converted into vasoconstriction (percent change in diameter after 370 microL/min flow: sham, 42+/-5%; CHF, -4+/-3%; P<0.05). Exercise partially restored FMD (18+/-3%; P<0.05 versus CHF). In sham rats, FMD was abolished by the nitric oxide-synthase inhibitor Nomega-nitro-L-arginine (L-NA) but unaffected by the cyclooxygenase inhibitor diclofenac or the free radical scavenger N-(2-mercaptopropionyl)-glycine (MPG). In arteries from sedentary CHF rats, FMD was not modified by L-NA, but it was partially restored by diclofenac or MPG. In exercised CHF rats, FMD was abolished by L-NA and only moderately improved by diclofenac or MPG. Likewise, endothelial nitric oxide synthase mRNA expression (determined by reverse transcription polymerase chain reaction at the level of the gracilis muscle) was reduced by CHF, and this was prevented by exercise. CONCLUSIONS CHF abolishes the FMD of small arteries by impairing the nitric oxide pathway, increasing oxidant stress, and releasing a prostanoid-contracting factor. Exercise partially restores FMD by increasing expression of endothelial nitric oxide synthase and preventing the production of vasoconstrictor prostanoids and free radicals. Such restoration of FMD might contribute to the increase in exercise capacity after physical exercise in CHF.

Toll-Like Receptors 2-Deficient Mice Are Protected Against Postischemic Coronary Endothelial Dysfunction

Objectives—Toll-like receptors (TLR) 2 are expressed in cardiac and inflammatory cells, and regulate leukocyte function. Because leukocyte adhesion is a critical event in endothelial injury induced by ischemia/reperfusion (I/R), we assessed whether TLR2 were involved in I/R - induced coronary endothelial injury. Methods and Results—Ischemia - reperfusion markedly decreased NO-mediated coronary relaxations to acetylcholine assessed ex vivo. In contrast, in TLR2 deficient mice, I/R paradoxically improved the NO-mediated responses to acetylcholine. To precise the cellular compartment expressing TLR2 which is involved in endothelial injury, we developed bone-marrow chimeric mice by transplanting TLR2−/− bone marrow to WT mice or WT bone marrow to TLR2−/− mice and submitted them to I/R 5 weeks after transplant. Both chimeric mice displayed similar protection as TLR2−/− mice against I/R-induced endothelial dysfunction, suggesting a role of TLR2 expressed on both non-bone marrow cells (in our case presumably endothelial cells and/or cardiomyocytes) and cells of bone marrow origin (presumably neutrophils). TLR2 deficiency was also associated with a smaller infarct size, and reduced reperfusion-induced production of reactive oxygen species and leukocyte infiltration. Conclusions—TLR2 contribute to coronary endothelial dysfunction after I/R, possibly through stimulation of neutrophil- (and free radical-) mediated endothelial injury.

Brachial Pressure–Independent Reduction in Carotid Stiffness After Long-Term Angiotensin-Converting Enzyme Inhibition in Diabetic Hypertensives

Hypertension and diabetes are associated with an increased arterial stiffness. A direct blood pressure–independent effect of angiotensin-converting enzyme inhibitors on arterial stiffness has never been unequivocally demonstrated. In this mechanistic study, we used an experimental design in which patients responding to 1 month treatment with 4 mg perindopril were randomized double-blind to either 4 mg perindopril or 8 mg perindopril for 6 months. We determined carotid distensibility with echotracking and applanation tonometry at baseline and after the 7-month treatment period in 57 essential hypertensive patients with type 2 diabetes (age 63±7 years). We monitored ambulatory blood pressure at baseline and after treatment. After 7 months treatment, 24-hour ambulatory blood pressure significantly decreased, with no significant difference between 4 mg and 8 mg perindopril. Carotid distensibility increased more after 8 mg perindopril compared with 4 mg perindopril (8 mg: from 13.1±5.9 to 16.0±6.7 kPa−1×10−3; 4 mg: from 13.2±5.2 to 12.7±5.9 kPa−1×10−3; ANOVA, dose-period interaction, P<0.05). Carotid internal diameter and elastic modulus were significantly lower after 8 mg perindopril compared with 4 mg perindopril, independent of blood pressure reduction. These results indicate a dose-dependent and blood pressure–independent reduction in carotid stiffness under chronic treatment with an angiotensin-converting enzyme inhibitor. They suggest that arterial distensibility was increased through an inward remodeling, leading to a reduction in wall stress, thus reducing elastic modulus. They also suggest that long-term administration of high doses (8 mg) of perindopril is required to improve carotid structure and function in hypertensive patients with type 2 diabetes.

Tendinous disorders attributed to statins: A study on ninety-six spontaneous reports in the period 1990–2005 and review of the literature

OBJECTIVE To date, statins have more often been considered a safe medication. However, with the wider use of statins, severe side effects have also been reported to occur in statin-treated patients, especially myositis and rhabdomyolysis. Currently, however, statin-associated tendon impairment has only been described anecdotally. The aim of this retrospective study was to evaluate tendon manifestations occurring in statin-treated patients. METHODS All reports in which a statin was listed spontaneously as a causative suspect medication of tendon complications in the network of the 31 French Pharmacovigilance Centers from 1990-2005 were included in this study. Data collection included patient characteristics and tendon adverse effects (time to onset of adverse effects, pattern, site of injury, and outcome). The percentage of the reports was further calculated for each statin. RESULTS Data were collected from 96 patients with a median age of 56 years; patients exhibited tendinitis (n = 63) and tendon rupture (n = 33). Tendinopathy more often occurred within the first year after statin initiation (59%). Tendon manifestations were related to atorvastatin (n = 35), simvastatin (n = 30), pravastatin (n = 21), fluvastatin (n = 5), and rosuvastatin (n = 5). Statin was reinitiated in 7 patients, resulting in recurrence of tendinopathy in all cases. CONCLUSION Our series suggests that statin-attributed tendinous complications are rare, considering the huge number of statin prescriptions. We suggest that prescribers should be aware of tendinous complications related to statins, particularly in risky situations, including physical exertion and association with medications known to increase the toxicity of statins.

Endothelial protective effects of preconditioning

The consequences of cardiac ischemia-reperfusion are not limited to myocytes but also extend to the coronary endothelium, where they are characterized by decreased nitric oxide (NO)-dependent relaxations. Given the essential role of the endothelium and NO in the regulation of vascular tone as well as platelet and leukocyte function, protection of coronary endothelial cells is an important therapeutic target. In this context, several studies have shown that both early and delayed preconditioning may prevent endothelial dysfunction after index ischemia-reperfusion. This endothelial protection most likely results from the inhibitory effects of preconditioning on expression of endothelial adhesion molecules, resulting in reduced neutrophil-endothelial interactions. The mechanisms of early endothelial preconditioning resemble those described at the level of the myocytes, and may involve mediators such as adenosine, bradykinin, NO and free radicals, together with activation of protein kinase C and opening of ATP-sensitive potassium channels. With regard to delayed preconditioning, recent studies have shown that both NO and free radicals are involved as triggers of this second window of endothelial protection. The complex interactions between these two radical species ultimately lead to a delayed increase in NO production, most likely responsible for the decreased adhesion of neutrophils to endothelial cells. Further identification of the triggers and mediators of this endothelial protection will allow the development of new therapeutic agents targeting both the myocardium and the coronary vasculature.