Transthyretin amyloid polyneuropathy in France: A cross-sectional study with 413 patients and real-world tafamidis meglumine use (2009-2019).

OBJECTIVE: We aimed to describe characteristics of patients with ATTR variant polyneuropathy (ATTRv-PN) and ATTRv-mixed and assess the real-world use and safety profile of tafamidis meglumine 20mg. METHODS: Thirty-eight French hospitals were invited. Patient files were reviewed to identify clinical manifestations, diagnostic methods, and treatment compliance. RESULTS: Four hundred and thirteen patients (296 ATTRv-PN, 117 ATTRv-mixed) were analyzed. Patients were predominantly male (68.0%) with a mean age of 57.2±17.2 years. Interval between first symptom(s) and diagnosis was 3.4±4.3 years. First symptoms included sensory complaints (85.9%), dysautonomia (38.5%), motor deficits (26.4%), carpal tunnel syndrome (31.5%), shortness of breath (13.3%), and unexplained weight loss (16.0%). Mini-invasive accessory salivary gland or punch skin and nerve biopsies were most common, with a performance of 78.8-100%. TTR genetic sequencing, performed in all patients, revealed 31 TTR variants. Tafamidis meglumine was initiated in 156/214 (72.9%) ATTRv-PN patients at an early disease stage. Median treatment duration was 6.00 years in ATTRv-PN and 3.42 years in ATTRv-mixed patients. Tafamidis was well tolerated, with 20 adverse events likely related to study drug among the 336 patients. CONCLUSION: In France, ATTRv patients are usually identified early thanks to the national network and the help of diagnosis combining genetic testing and mini-invasive biopsies.

Imaging and modern assessment of the right ventricle.

The right ventricular function is difficult to assess owing to its complex morphology, structure and function. The right ventricle (RV) comprises three compartments, the inlet, the apex, and the outlet contracting with a peristaltic motion from the inflow to the outflow chamber and is tightly linked to left ventricular (LV) function through the pulmonary circulation, the interventricular septum and the myocardium inside the pericardial envelop. The relation of RV function to symptom occurrence, exercise capacity and prognosis in a wide variety of cardiac diseases emphasizes the usefulness of its routine assessment. The evaluation of the RV is largely carried out by echocardiography in daily clinical practice despite important limitations inherent to two-dimensional imaging. Multiple views and numerous parameters allow clinicians to integrate the RV function in the clinical decision-making process. Recent modalities of echocardiography such as myocardial deformation and three-dimensional imaging or exercise echocardiography are promising tools for the assessment of the RV. Cardiac magnetic resonance imaging provides the unique opportunity to image the RV in motion and in three dimensions without the limitation of echogenicity. Therefore, cardiac magnetic resonance imaging is taking a growing place in the assessment of the RV in a wide variety of cardio-pulmonary diseases as pulmonary hypertension, ischemia, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, heart failure or congenital heart diseases. Integrating the complex interplay between both ventricles and the pulmonary circulation, this review will discuss the latest results of standard and novel techniques allowing the assessment of RV function by echocardiography and cardiac magnetic resonance imaging, and will provide to the clinicians, facing therapeutic challenges, a comprehensive overview of right heart function.

Antibiotic prophylaxis of infective endocarditis in patients with predisposing cardiac conditions: French cardiologists' implementation of current guidelines.

BACKGROUND: To prevent infective endocarditis (IE), with the exception of the United Kingdom, antibiotic prophylaxis (AP) is recommended in patients with predisposing cardiac conditions (PCCs) worldwide. To conclude on the relevance of this strategy, how the current guidelines are applied is a crucial point to investigate. The first aim of this study was to assess cardiologists' implementation of the current guidelines. The secondary objective was to identify specific areas where the training and knowledge of French cardiologists could be improved. METHODS: A national online survey was carried out among the 2228 cardiologist members of the French Society of Cardiology. RESULTS: The high risk PCCs for which IE AP is recommended were correctly identified by the vast majority of the respondents so that IE AP is mostly prescribed correctly in such patients. But only 12% identified all the right indications for IE AP according to 13 predefined PCCs (3 at high-risk, 6 at moderate-risk and 4 at low-risk of IE) so that some IE AP misuses are recorded, overprescription in particular. Only 47% prescribed the proper amoxicillin schedule and only 15% prescribed the appropriate clindamycin schedule in cases with penicillin allergy. CONCLUSION: This study evidenced relevant areas where the training of cardiologists could be improved such as knowledge of the risk of IE for certain PCCs and some common invasive dental procedures. Cardiologists' knowledge should be improved before any conclusion can be drawn on the relevance of this AP strategy and its influence on IE incidence.

The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle.

Beta1- and beta2-adrenoceptors in heart muscle cells mediate the catecholamine-induced increase in the force and frequency of cardiac contraction. Recently, in addition, we demonstrated the functional expression of beta3-adrenoceptors in the human heart. Their stimulation, in marked contrast with that of beta1- and beta2-adrenoceptors, induces a decrease in contractility through presently unknown mechanisms. In the present study, we examined the role of a nitric oxide (NO) synthase pathway in mediating the beta3-adrenoceptor effect on the contractility of human endomyocardial biopsies. The negative inotropic effects of a beta3-adrenoceptor agonist, BRL 37344, and also of norepinephrine in the presence of alpha- and beta1-2-blockade were inhibited both by a nonspecific blocker of NO, methylene blue, and two NO synthase (NOS) inhibitors, L-N-monomethyl-arginine and L-nitroarginine-methyl ester. The effect of the NOS inhibitors was reversed by an excess of L-arginine, the natural substrate of NOS, but not by D-arginine. Moreover, the effects of the beta3-adrenoceptor agonist on contractility were associated with parallel increases in the production of NO and intracellular cGMP, which were also inhibited by NOS inhibitors. Immunohistochemical staining of human ventricular biopsies showed the expression of the endothelial constitutive (eNOS), but not the inducible (iNOS) isoform of NOS in both ventricular myocytes and endothelial cells. These results demonstrate that beta3-adrenoceptor stimulation decreases cardiac contractility through activation of an NOS pathway. Changes in the expression of this pathway may alter the balance between positive and negative inotropic effects of catecholamines on the heart potentially leading to myocardial dysfunction.

Churg-Strauss syndrome revealed by granulomatous acute pericarditis: two case reports and a review of the literature.

BACKGROUND: Churg-Strauss syndrome (CSS) is a necrotizing systemic vasculitis with extravascular granulomas and eosinophilic infiltrates of small vessels. CSS is usually revealed by nonspecific signs of necrotizing vasculitis in a context of late-onset asthma and blood eosinophilia. It is considered a systemic vasculitis with the highest prevalence of cardiac involvement and can lead to rapid-onset heart failure due to specific cardiomyopathy. Pericardial effusion may also occur during CSS and is usually well tolerated. OBJECTIVE: The objective of these case reports was to indicate that CSS may present as tamponade, with or without other visceral involvement. METHODS: Among CSS patients treated during the past 10 years at 2 French university hospitals, we have identified and described 2 cases revealed by tamponade with pericardial biopsy-proven granulomatous vasculitis. We have also reviewed the international medical literature in PubMed on cardiac involvement in CSS. RESULTS: The first case report describes a 66-year-old man who had an isolated cardiac tamponade with both inflammatory syndrome and eosinophilia. Long-term remission was obtained with corticosteroids. The second case report describes a 46-year-old woman whose CSS presented with tamponade and associated central nervous system and myocardial involvement. Remission was obtained with corticosteroids and cyclophosphamide. In both cases, CSS was assessed by histological analysis of a pericardial sample. CONCLUSIONS: CSS may present as isolated cardiac tamponade. Whereas pericarditis with myocardial injury warrants immunosuppressive therapy, isolated pericarditis without other visceral involvement of poor prognosis only requires corticosteroid therapy.

[Therapeutic education for heart failure: a necessity in 2007]. / Education thérapeutique pour l'insuffisance cardiaque: une nécessité en 2007.

Heart failure is a severe illness, marked with a still too high morbidity and mortality. Therapeutic education, fundamental for any chronic pathology, is taking a more and more important place in heart failure. Its value has been proved, and its importance in the multidisciplinary management of heart failure patients has been confirmed in terms of improving the prescription of medical treatment and allowing a better quality of life. France was late to recognise this technique, but the successful development of the I-CARE programme should contribute to improving both the quality of care for patients and the understanding of this pathology.

[Genetic aspects of valvulopathies]. / Aspects Génétiques des Valvulopathies.

Valvular dystrophies due to myxoid degeneration are common and potentially serious cardiac pathologies. They constitute a heterogeneous group of which the most usual is idiopathic mitral valvular prolapse (Barlow's disease). The majority of mitral valvular prolapses are sporadic, but there are several familial forms. Transmission is usually autosomal dominant with incomplete penetrance and variable expression. The first chromosomal location to be identified was on the 16p11-13 chromosome. Since then, two other loci have been identified on the 11p15.4 and 13q31-32 chromosomes. Our team has recently identified the first gene responsible for myxoid valvulopathy linked to the X chromosome, from a large family of 318 members. This is the gene that codes for filamin A, which is a cytoskeleton protein. The frequency of mutations in this gene is still unknown, but out of 7 families in which transmission was compatible with X-linked transmission, mutations were discovered in 4 of the families. Thanks to a genetic epidemiological approach, we have also demonstrated that there are familial forms of aortic stenosis, which are probably common. Identification of the genes implicated in these common forms of valvular pathology is important, as it will allow a better understanding of the pathophysiology of these valvular disorders and could lead to better therapeutic management in the future.

Predictors of Health-Related Quality of Life Decline after Transcatheter Aortic Valve Replacement in Older Patients with Severe Aortic Stenosis.

BACKGROUND: Transcatheter aortic-valve implantation (TAVI) has been shown to improve survival and quality of life in patients with severe aortic stenosis. However, one-third of patients have poor outcome as death, functional decline or quality of life (QoL) decline. The aim of this study was to determine cardiac and geriatric predictors of physical and mental QoL decline 6 months after a TAVI procedure in patients aged 75 and older. METHODS: Between January 2013 and June 2014, we did a prospective and multicenter study including patients ≥ 75 years old referred for TAVI. The primary outcome was the measure of QoL, assessed by the Short Form 36 survey (SF-36), before and 6 months after the intervention. Association between QoL decline and baseline characteristics including cardiac and geriatric factors was analysed by logistic regression models. RESULTS: Mean age of the 150 patients studied was 83.7 years old and 56% were men. The primary end point, mean SF-36 physical summary score, significantly improved between baseline and 6-month (33.6 vs. 36.4, p=0.003) whereas mental component score significantly decreased (48.2 vs. 36.4, p-value<0.001). However, patients with presence of depressive symptoms before the intervention had mental QoL improvement at six months (OR 0.04 [0.01-0.19], p-value<0.001) and no significant geriatric predictors were associated with physical QoL decline. CONCLUSION: The mental QoL significantly decreased and patients with preoperative depressive symptoms had mental QoL improvement at six months. Researches are needed to confirm that mental QoL of patients with depressive symptoms can be improved by TAVI.

Role of endothelium-derived nitric oxide in the regulation of cardiac oxygen metabolism: implications in health and disease.

Endothelium-derived NO is considered to be primarily an important determinant of vascular tone and platelet activity; however, the modulation of myocardial metabolism by NO may be one of its most important roles. This modulation may be critical for the regulation of tissue metabolism. Several physiological processes act in concert to make endothelial NO synthase-derived NO potentially important in the regulation of mitochondrial respiration in cardiac tissue, including (1) the nature of the capillary network in the myocardium, (2) the diffusion distance for NO, (3) the low toxicity of NO at physiological (nanomolar) concentrations, (4) the fact that low PO(2) in tissue facilitates the action of NO on cytochrome oxidase, and (5) the formation of oxygen free radicals. A decrease in NO production is involved in the pathophysiological modifications that occur in heart failure and diabetes, disease states associated with altered cardiac metabolism that contributes to the evolution of the disease process. In contrast, several drugs (eg, angiotensin-converting enzyme inhibitors, amlodipine, and statins) can restore or maintain endogenous production of NO by endothelial cells, and this mechanism may explain part of their therapeutic efficiency. Thus, the purpose of this review is to critically evaluate the role of NO in the control of mitochondrial respiration, with special emphasis on its effect on cardiac metabolism.

Recurrence of dilated cardiomyopathy after re-introduction of a tricyclic antidepressant.

A causal relationship between treatment with tricyclic antidepressant (TCA) at therapeutic doses and cases of dilated cardiomyopathy has been suspected, but not definitely evidenced. We present a case of a dilated cardiomyopathy, which seemed idiopathic, but occurred during treatment with imipramine and recovered after its withdrawal. For the first recorded time, the cardiomyopathy recurred 9 years later, after a 2-year period of treatment with amitriptyline and lithium, and recovered again 1 year after both psychotropic drugs withdrawal. New arguments for the existence of TCA-induced dilated cardiomyopathy are brought.

Heart failure with preserved systolic function: a diagnostic algorithm for a pragmatic definition.

Heart failure is a major health problem which often concerns the elderly. Prevalence of heart failure with preserved systolic function is increasing and varies from 40 to 50%. In the literature, and in the large epidemiological studies, it is commonly designed with the term of "diastolic heart failure", even if a precise analysis of diastolic function is not performed. A diagnostic algorithm is proposed in order to better define the concept of heart failure with preserved systolic function. It consists of seven steps from symptoms and clinical signs to the echocardiographic analysis of diastolic function, in order to confirm the definition of heart failure with preserved systolic function.

[Importance of therapeutic education in the multidisciplinary management of heart failure]. / Importance de l'education thérapeutique dans la prise en charge multidisciplinaire de l'insuffisance cardiaque.

Heart failure is a severe disease with high morbidity and mortality rates. The interest for multidisciplinary heart failure patient management is increasing in order to improve prescription of medical therapies and to allow a better quality of life. Proofs of reduction in morbi-mortality exist and some models of management have been assessed. The most important point remains the major role of therapeutic education. Training of health care professionals is needed. Tools for therapeutic education have been created and can be associated with complementary informative means. All these elements allow that a new approach of heart failure takes in place in France.

[Main issues and contributions of the evaluation of health care networks]. / Les problématiques et les apports de l'evaluation d'un réseau de santé.

Health care networks correspond to a form of horizontal and flexible organisation, which consists in dealing with complex problems of health and long-term care. Networks rest entirely on the mechanisms of coordination between the various actors of care, whose keystone is the medical information flow. The challenge of the health networks evaluation is to prove the added value of a network organization, instead of a conventional disease-centred health care. The evaluation of health care networks is legally required but not sustained by specialists. Evaluation must ensure the existence of a real management; measure the interest of health care professionals and the impact of the network on professional practices. Moreover, evaluation accompanies the development of the network and offers the advisability to the decision maker of obtaining a tool for control of management, i.e. an information tool and a decision-making help, with the aim of a continuous improvement of the quality of care. However the absence of formation of the medical coordinators to management, makes networks management problematic. Thus, health care networks cannot make the saving in a good administrative and management base. In the same way health care networks must obtain an information system adapted to their type of coordination, allowing the evaluation required by the financier.

Intramyocardial transplantation of mesenchymal stromal cells for chronic myocardial ischemia and impaired left ventricular function: Results of the MESAMI 1 pilot trial.

BACKGROUND: The MESAMI 1 trial was a bicentric pilot study designed to test the feasibility and safety of intramyocardially injected autologous bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of ischemic cardiomyopathy. METHODS AND RESULTS: The study included 10 patients with chronic myocardial ischemia, left ventricular (LV) ejection fractions (EFs) of ≤35%, and reversible perfusion defects who were on stable optimal medical therapy and were not candidates for revascularization. MSCs (mean: 61.5×10(6) cells per patient) were injected into 10-16 viable sites at the border of the LV scar via a NOGA-guided catheter. Both primary endpoints, feasibility (successful harvest, expansion, and injection of autologous MSCs) and safety (absence of severe adverse events [SAEs]) were met in all 10 patients at the 1-month follow-up time point, and none of the SAEs reported during the full 2-year follow-up period were attributable to the study intervention. The results of secondary efficacy endpoint analyses identified significant improvements from baseline to Month 12 in LVEF (29.4±2.0% versus 35.7±2.5%; p=0.003), LV end-systolic volume (167.8±18.8mL versus 156.1±28.6mL; p=0.04), 6-min walk test and NYHA functional class. CONCLUSIONS: Our results suggest that autologous MSCs can be safely administered to the hearts of patients with severe, chronic, reversible myocardial ischemia and impaired cardiac function and may be associated with improvements in cardiac performance, LV remodeling, and patient functional status. A randomized, double blind, multicenter, placebo-controlled clinical trial (MESAMI 2) will evaluate the efficacy of this treatment approach in a larger patient population. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT01076920.

Upregulation of beta(3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium.

BACKGROUND: Contrary to beta(1)- and beta(2)-adrenoceptors, beta(3)-adrenoceptors mediate a negative inotropic effect in human ventricular muscle. To assess their functional role in heart failure, our purpose was to compare the expression and contractile effect of beta(3)-adrenoceptors in nonfailing and failing human hearts. METHODS AND RESULTS: We analyzed left ventricular samples from 29 failing (16 ischemic and 13 dilated cardiomyopathic) hearts (ejection fraction 18.6+/-2%) and 25 nonfailing (including 12 innervated) explanted hearts (ejection fraction 64.2+/-3%). beta(3)-Adrenoceptor proteins were identified by immunohistochemistry in ventricular cardiomyocytes from nonfailing and failing hearts. Contrary to beta(1)-adrenoceptor mRNA, Western blot analysis of beta(3)-adrenoceptor proteins showed a 2- to 3-fold increase in failing compared with nonfailing hearts. A similar increase was observed for Galpha(i-2) proteins that couple beta(3)-adrenoceptors to their negative inotropic effect. Contractile tension was measured in electrically stimulated myocardial samples ex vivo. In failing hearts, the positive inotropic effect of the nonspecific amine isoprenaline was reduced by 75% compared with that observed in nonfailing hearts. By contrast, the negative inotropic effect of beta(3)-preferential agonists was only mildly reduced. CONCLUSIONS: Opposite changes occur in beta(1)- and beta(3)-adrenoceptor abundance in the failing left ventricle, with an imbalance between their inotropic influences that may underlie the functional degradation of the human failing heart.

Clinical characteristics of a familial inherited myxomatous valvular dystrophy mapped to Xq28.

OBJECTIVES: The purpose of this study was to describe the phenotypic characteristics of an inherited myxomatous valvular dystrophy mapped to Xq28. BACKGROUND: Myxomatous valve dystrophies are a frequent cause of valvular diseases, the most common being idiopathic mitral valve prolapse. They form a group of heterogeneous diseases difficult to subclassify. The first mapping of the gene for a myxoid valvular dystrophy to Xq28 allowed investigation of the phenotype of affected members in a large family and characterization of the disease. METHODS: Among the 318 members in the pedigree, 89 agreed to participate in this study. Phenotypic characteristics were investigated using clinical examination, transthoracic echocardiography and biological analysis (F.VIII activity). Genetic status was based on haplotype analysis. RESULTS: Among 46 males, 9 were hemizygous to the mutant allele and had an obvious mitral and/or aortic myxomatous valve defect, and 4 had undergone valvular surgery. All had typical mitral valve prolapse associated in six cases with moderate to severe aortic regurgitation. The valve defect cosegregated with mild hemophilia A (F.VIII activity = 0.32 +/- 0.05). The 37 remaining males had normal valves and normal F.VIII activity. Heterozygous women were identified on the basis of their haplotypes. Among the 17 women heterozygous to the mutant allele, moderate mitral regurgitation was present in 8, associated with mild mitral valve prolapse in 1 and aortic regurgitation in 3, whereas 2 women had isolated mild aortic regurgitant murmur. In heterozygotes, the penetrance value was 0.60 but increased with age. CONCLUSION: X-linked myxomatous valvular disease is characterized by mitral valve dystrophy frequently associated with degeneration of the aortic valves affecting males and, to a lower severity, females. The first localization of a gene for myxomatous valvular diseases is the first step for the subclassification of these diseases.

[Viral cardiomyopathy]. / Cardiomyopathies virales. A propos de 4 observations d'infection myocardique à parvovirus B-19 et revue de la littérature.

In too many cases, the cause of dilated cardiomyopathy (DCM) remains undetermined. Coronary or valvular heart diseases, connective tissue disorders, toxic causes and signs of infection are systematically investigated. With the exceptions of coronary and sometimes valvular heart disease, the treatment of cardiac failure remains symptomatic treating the consequences but not the cause of DCM, which is therefore diagnosed as "idiopathic". This artericle reports the clinical history of 4 patients followed up for apparently "idiopathic" DCM in whom the presence of chronic Parvovirus B-19 infection was demonstrated. Based on these 4 cases, the hypothesis of an infectious cause of DCM and the role of myocardial biopsy, given the progress in molecular biology, are reconsidered. Parvovirus B-19 infection has recently been recognised not only as a cause of myocarditis but also of chronic viral cardiomyopathy, as in adeno and enteroviral infection. The authors conclude that the progress in molecular biology, the recognition of a viral aetiology and the efficacy of immuno-modulator therapy such as beta-interferon, may lead to a new management strategy of patients with DCM in cardiological referral centres.

[Therapeutic education for cardiac failure patients: the I-care programme]. / Education thérapeutique des patients insuffisants cardiaques: le programme I-care.

Therapeutic education is becoming increasingly important in the management of chronic diseases including cardiac failure. The I-CARE programme consists of an evaluation of the role of therapeutic education in France, creating standardised tools and setting up training sessions for therapeutic education in the context of cardiac failure. Approximately two thirds of the French centres contacted perform therapeutic education with their available means. The lack of personnel, space, and training tools represent obstacles to the development of therapeutic education. The tools developed in the programme fall into 5 areas: diagnosis education, understanding the illness, diet, physical activity/daily life, and treatment. Training sessions were organised for the teams, consisting of at least one cardiologist and nurse. The I-CARE programme should allow the expansion of therapeutic education for cardiac failure and improve the multidisciplinary management of this disease which increasingly affects often elderly subjects.

Determinants in treatment decision-making in older patients with symptomatic severe aortic stenosis.

BACKGROUND: Three treatment options are available for patients with aortic stenosis: surgical aortic valve replacement (SAVR), transcatheter aortic valve implantation (TAVI) and medical treatment (MT). However, little is known about how Heart Team treatment decisions are made under routine conditions. The aim of this study was to identify the cardiac and geriatric components associated with treatment decision-making in older patients with symptomatic severe aortic stenosis. METHODS: Between 2011 and 2013, 337 consecutive patients ≥75 years old referred for pre-operative evaluation in Nantes University Hospital had a comprehensive cardiac and geriatric assessment. In this observational retrospective study, relationships between treatment decision-making and cardiac or geriatric components were evaluated through multivariable models. RESULTS: Surgical aortic valve replacement was proposed to 108 patients, TAVI to 131 and medical treatment to 98 patients. Mean age was 83±4 years and 51% were women. Geriatric components associated with treatment decision-making between SAVR vs. TAVI were age (p<0.001, OR=0.790), comorbidity score (p=0.027, OR=0.86), functional status (p<0.001, OR=1.46), and gait speed (p<0.001, OR=0.23). Cardiac components associated with decision-making between SAVR vs. TAVI were history of previous cardiac surgery (p<0.001, OR=0.09), left ventricular ejection fraction <50% (p<0.001, OR=0.14), coronary artery disease requiring revascularization (p=0.019, OR=0.4). Between TAVI vs. medical treatment, only history of previous cardiac surgery and presence of another severe valve disease were significant. CONCLUSION: Comorbidities, functional status and physical performance, were significantly associated with the consensual treatment decision-making, independently of cardiac components in older patients with symptomatic severe aortic stenosis.

Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta.

1. The relaxant effects of isoprenaline may result from activation of another beta-adrenoceptor subtype in addition to beta1 and beta2. This study evaluated the role of a third beta-adrenoceptor subtype, beta3, in beta-adrenoceptor-induced relaxation of rat thoracic aorta by isoprenaline. 2. Isoprenaline produced a concentration-dependent relaxation of phenylephrine pre-contracted rings of the thoracic aorta (pD2=7.46+/-0.15; Emax=85.9+/-3.4%), which was partially attenuated by endothelium removal (Emax=66.5+/-6.3%) and administration of the nitric oxide (NO) synthase inhibitor, L-NG-monomethyl arginine (L-NMMA) (Emax=61.3+/-7.9%). 3. In the presence of nadolol, a beta1- and beta2-adrenoceptor antagonist, isoprenaline-induced relaxation persisted (Emax=55.6+/-5.3%), but occurred at higher concentrations (pD2=6.71+/-0.10) than in the absence of nadolol and lasted longer. 4. Similar relaxant effects were obtained with two beta3-adrenoceptor agonists: SR 58611 (a preferential beta3-adrenoceptor agonist), and CGP 12177 (a partial beta3-adrenoceptor with beta1- and beta2-adrenoceptor antagonistic properties). SR 58611 caused concentration-dependent relaxation (pD2=5.24+/-0.07; Emax=59.5+/-3.7%), which was not modified by pre-treatment with nadolol but antagonized by SR 59230A, a beta3-adrenoceptor antagonist. The relaxation induced by SR 58611 was associated with a 1.7 fold increase in tissue cyclic GMP content. 5 Both relaxation and the cyclic GMP increase induced by SR 58611 were greatly reduced by endothelium removal and in the presence of L-NMMA. 6 We conclude that in the rat thoracic aorta, beta3-adrenoceptors are mainly located on endothelial cells, and act in conjuction with beta1- and beta2-adrenoceptors to mediate relaxation through activation of an NO synthase pathway and subsequent increase in cyclic GMP levels.