Heart failure and left ventricular dysfunction are major causes of morbidity and mortality. In this thesis, metabolic, hormonal, genetic and prognostic aspects of echocardiographically determined left ventricular function were investigated in a fairly large longitudinal population-based study of men. The participants were examined both at age 50 and 70 years and were followed for mortality using the national cause-of-death registry. Several factors associated with the insulin resistance syndrome predicted left ventricular systolic dysfunction independent of myocardial infarction, hypertension, diabetes and the use of cardiovascular medication after twenty years follow-up. Plasma levels of N-terminal atrial natriuretic peptide (N-ANP) were significantly increased in men with left ventricular dysfunction in comparison to healthy men. However, the diagnostic accuracy was poor due to the extensive overlapping between the groups. Relations between a haplotype of the novel hUNC-93B1 gene and the E/A-ratio were found and validated in separate samples of the cohort. Myocardial performance index (a Doppler derived index of combined left ventricular systolic and diastolic function) and left ventricular ejection fraction were found to be predictors for cardiovascular mortality independent of traditional cardiovascular risk factors in a longitudinal analysis with a mean follow-up of seven years. In conclusion, this thesis showed that left ventricular function is influenced by metabolic, hormonal and genetic factors and that echocardiographic measurements of left ventricular function, such as the myocardial performance index, are strong independent risk factors for cardiovascular mortality in elderly men.

Positron Emission Tomography (PET) permits regional myocardial perfusion, fibrosis and oxidative metabolism to be non-invasively quantified with radioactive tracers such as [15O]-water and [1-11C]-acetate. PET is an established research tool in congestive heart failure (CHF), a major cause of morbidity and mortality. However, as CHF is a syndrome that eventually affects all aspects of cardiac and systemic hemodynamic function, more clinically relevant information from a single PET scan is desirable. The aim of this thesis therefore was to develop and implement some new concepts in cardiac PET. A new method for the measurement of cardiac output with any tracer was validated in animal experiments and CHF patients. The early pulmonary retention of [1-11C]-acetate was inversely related to left ventricular (LV) function in animals and was directly proportional to lung water content and severity of LV diastolic dysfunction in patients. Eight patients with acute myocardial infarction were followed with serial PET from 3 hours to 3 weeks after trombolytic treatment. PET revealed that myocardial perfusion and the extraction and utilization of fuel substrates all decreased closer to the infarct centre. The rate of oxygen utilization within the infarct at 3 h predicted degree of myocardial fibrosis, pulmonary oedema and tissue viability at 3 weeks. Seventeen patients with CHF due to chronic ischemic cardiomyopathy and severely reduced LV function were evaluated with [1-11C]-acetate PET before and after coronary artery bypass surgery. There was a dramatic improvement in physical performance and symptoms, which was not correlated to the standard LV ejection indices. PET revealed that functional improvement was associated with improved LV loading conditions, reversed remodeling and homogenization of oxidative metabolism rather than increased output.

Background - Regular exercise reduces the risk of cardiovascular disease and subsequent sudden cardiac death (SCD). However, a small, but notable proportion of athletes die suddenly due to inherited or congenital disorders of the heart that predispose to malignant ventricular arrhythmias. Such tragedies are highly publicised, particularly when high-profile athletes are involved. To date, limited evidence for the efficacy of cardiovascular pre-participation screening exists outside of the Italian experience. Furthermore, limited data exists examining the impact of ethnicity on cardiac adaptations to physical training. Whilst the cardiovascular benefits of exercise are well known, the impact of life-long endurance exercise is less well understood. Long term high-intensity endurance exercise is associated with changes in cardiac morphology together with electrocardiographic alterations that are believed to be physiologic in nature. Recent data however, has suggested a number of deleterious adaptive changes in cardiac structure, function and electrical activity in response to life-long endurance activity. Aims and Objectives - The aims of this PhD were; 1) To find an effective preparticipation screening method that would successfully identify pre-existing cardiovascular abnormalities, 2) To identify the prevalence of hypertrophic cardiomyopathy and Long QT syndrome in elite UK athletes; 3) To examine the impact and significance of ethnicity upon left ventricular remodelling in elite athletes, and 4) To examine the acute and chronic impact of ultra-endurance exercise across the life-span in male endurance athletes. Major Results and Conclusions – 1) Study 2 sought to confirm the efficacy of resting 12-Lead ECG ‘alongside’ personal/family history questionnaires and physical examinations as collective tools to identify diseases that have the potential of causing sudden death within a cohort of elite junior athletes (n=1074) and physically active school children (n=1646). Nine participants were identified with a positive diagnosis of a disease associated with SCD. None of those diagnosed with a disease associated with SCD were symptomatic or had a family history of note. Thus, personal symptoms and family history questionnaires alone are inadequate in the identification of individuals with diseases associated with SCD. In conclusion, resting 12-Lead ECG is paramount when screening for diseases that have the potential of causing sudden death in the young. 2) Study 3 examined 3,500 asymptomatic elite athletes (75% male) with a mean age of 20.5 ± 5.8 years with 12-lead ECG and 2-dimensional echocardiography. None had a known family history of HCM. Of the 3,500 athletes, 53 (1.5%) had LVH (mean 13.6 ± 0.9mm, range 13 to 16mm), and of these 50 had a dilated LV cavity with normal diastolic function to indicate physiological left ventricular hypertrophy. Three (0.08%) athletes with LVH had a non-dilated LV cavity and associated deep T-wave inversion that could have been consistent with HCM. However, none of the 3 athletes had any other phenotypic features of HCM on further non-invasive testing and none had first-degree relatives with features of HCM. In conclusion, the prevalence of HCM in elite athletes is significantly less than in the general population; with the demands of strenuous exercise on the cardiovascular system selecting out most individuals with HCM. Study 4 examined 2000 elite athletes in order to identify the prevalence of Long QT syndrome. Three athletes had a QTc value of >500 ms and all exhibited one of: paradoxical prolongation of QTc during exercise, a confirmatory genetic mutation, or prolonged QTc in a first-degree relative. In contrast, none of the athletes with a QTc value of <500 ms had any other features to indicate LQTS. Accordingly, the prevalence of a prolonged QTc interval in elite British athletes is 0.4%. 3) Study 6 examined 300 nationally ranked UK black male athletes (mean age 20.5 years) in comparison to 150 black and white sedentary individuals and 300 highly-trained white male athletes. Black athletes exhibited greater LV wall thickness and cavity size compared with sedentary black and white individuals. Black athletes had greater LV wall thickness compared with white athletes. A minority of black athlete’s exhibit LVH ≥15 mm; proposing that in the absence of cardiac symptoms or a family history of HCM, an LV wall thickness ≥15 mm in black athletes may represent physiologic LVH when the LV cavity is enlarged and diastolic indexes are normal. 7 black athletes (12%) with LVH displaying deep T-wave inversions in leads V1 to V4. In conclusion, in the absence of obvious pathology, these electrical anomalies in black athletes likely represent a normal spectrum of ECG changes in response to physical training. 4) Study 8 examined 17 male participants (age 33.5 ± 6.5 years, 26–40 years) using cardiac magnetic resonance (CMR) and echocardiography before and after a marathon to investigate the relationship between systolic function and diastolic function against biomarkers of cardiac damage. Results demonstrates biomarkers of myocardial cell damage following an acute bout of prolonged exercise are not associated with either systolic or diastolic functional measures, and do not seem to be associated with any detectable myocardial inflammation, oedema, or scarring using either gold standard techniques of gadolinium enhanced CMR or echocardiography respectively. The impact of multiple episodes of prolonged exercise, as experienced by highly trained veteran endurance athlete is not fully understood. 5) Study 10 examined the cardiac structure and function of 12 life-long, competitive endurance veteran athletes (> 50 yrs, mean ± SD marathons 178 ± 209 (range 20 – 650)) against 17 young male endurance athletes (<40 yrs) using echocardiography and CMR with late gadolinium enhancement (LGE) to assess myocardial fibrosis. Lifelong veteran athletes had smaller LV and RV end-diastolic and end-systolic volumes (p<0.05) but maintained LV and RV systolic function compared with young athletes. In 6 (50%) of the veteran athletes LGE of CMR indicated the presence of myocardial fibrosis; no LGE in the young athletes. The prevalence of LGE in veteran athletes was not associated with the number of competitive marathons or ultra-endurance marathons (>50 miles) completed, age, LV and RV end-diastolic volumes or LV mass (p>0.05). In conclusion, there is limited evidence at present demonstrating that cardiovascular re-modelling following lifelong endurance exercise leads to long-term disease progression, cardiovascular disability or SCD.

Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. The complex, interaction between the kidney and the cardiovascular system is incompletely understood, particularly at the early stages of the cardiovascular continuum. The overall aim of this thesis was to clarify novel aspects of the interplay between the kidney and the cardiovascular system at different stages of the cardiovascular continuum; from risk factors such as insulin resistance, inflammation and oxidative stress, via sub-clinical cardiovascular damage such as endothelial dysfunction and left ventricular dysfunction, to overt cardiovascular death. This thesis is based on two community-based cohorts of elderly, Uppsala Longitudinal Study of Adult Men (ULSAM) and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). The first study, show that higher insulin sensitivity, measured with euglycemic-hyperinsulinemic clamp technique was associated to improve estimated glomerular filtration rate (eGFR) in participants with normal fasting plasma glucose, normal glucose tolerance and normal eGFR. In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function during follow-up. In the second study, eGFR was inversely associated with different inflammatory markers (C-reactive protein, interleukin-6, serum amyloid A) and positively associated with a marker of oxidative stress (urinary F2-isoprostanes). In line with this, the urinary albumin/creatinine ratio was positively associated with these inflammatory markers, and negatively associated with oxidative stress. In study three, higher eGFR was associated with better endothelial function as assessed by the invasive forearm model. Further, in study four, higher eGFR was significantly associated with higher left ventricular systolic function (ejection fraction). The 5th study of the thesis shows that higher urinary albumin excretion rate (UAER) and lower eGFR was independently associated with an increased risk for cardiovascular mortality. Analyses of global model fit, discrimination, calibration, and reclassification suggest that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent cardiovascular disease. Conclusion: this thesis show that the interaction between the kidney and the cardiovascular system plays an important role in the development of cardiovascular disease and that this interplay begins at an early asymptomatic stage of the disease process.

No description available.

The scientific novelty of the study A large number of reports have demonstrated that depressed heart rate variability after myocardial infarction (MI), left ventricular dysfunction and arrhythmias are powerful predictors of mortality. Nevertheless there is a lack of detailed assessment of heart rate variability in the acute period of MI, especially during the first 24 hours, from long-term (24-h) recordings, and the value of different parameters of heart rate variability in predicting dangerous complications of MI was not fully evaluated. The indications of complex and constant monitoring of heart rate variability, left ventricular function, arrhythmias in acute MI are not based on scientific studies as well as their value in predicting the effect of different methods of management, course and outcomes of critical cardiac conditions. Thus, the current study differs from all the earlier studies in that we assessed heart rate variability in the very early period of myocardial infarction (the first and the third day) using long time recordings (24 h), both – time-domain and frequency-domain –methods, and evaluated its changes in relation to arrhythmias and left ventricular function, using not only conventional 2D-echocardiography but also left ventricular long axis function assessment by M-mode and tissue Doppler imaging. The aim of the study The aim of the study was to determine the association between heart rate variability, cardiac arrhythmias and left ventricular... [to full text]

Effet de l’atorvastatine sur la dysfonction endothéliale des artères coronaires épicardiques associée à l’hypertrophie ventriculaire gauche dans un modèle porcin Forcillo J, Aubin MC, Horn A, Shi YF, Carrier M, Tardif JC, Perrault LP Introduction: L’atorvastatine par ses effets pléiotropiques pourrait limiter la dysfonction endothéliale associée au développement de l’HVG. Méthodologie : Un cerclage de l’aorte ascendante pendant 2 mois entraîne le développement d’HVG et les groupes ont été traités avec atorvastatine 40 ou 80 mg de 60 à 90 jours. L’HVG est confirmée par échographie. La réactivité vasculaire est évaluée en chambres d’organe, la fonction endothéliale par la quantification de la GMPc et des nitrites/nitrates plasmatiques. Le stress oxydant est mesuré par les niveaux d’ANG II et de la carbonylation des protéines. Résultats : Après 60 et 90 j de cerclage, l’HVG est observée chez tous ces groupes. Les courbes concentrations-réponse des anneaux des artères coronaires épicardiques des groupes traités avec l’atorvastatine 40 et 80 mg pour 30 et 60 jours n’ont démontré aucune amélioration des relaxations dépendantes de l’endothélium. Une exacerbation significative de la dysfonction endothéliale a été observée. Les niveaux vasculaires de GMPc sont significativement diminués dans le groupe sans cerclage traité 60 d et ceux d’ANG II sont fortement augmentés chez ce dernier groupe ainsi que le groupe traité avec 80 mg pour 30 jours par rapport aux contrôles. L’expression de la carbonylation des protéines est augmentée dans le groupe témoin traité avec atorvastatine 80 mg, reflétant une augmentation du stress oxydant. Conclusion : L’administration d’atorvastatine ne prévient pas le développement de l’HVG ni la dysfonction endothéliale dans notre modèle. Au contraire l’atorvastatine à haute dose a un effet toxique sur les artères coronaires épicardiques en augmentant la dysfonction endothéliale. / Effect of atorvastatin on endothelial dysfunction of epicardial coronary arteries associated with left ventricular hypertrophy in a porcine model. Forcillo J, Aubin MC, Horn A, Shi YF, Carrier M, Tardif JC, Perrault LP Background: Atorvastatin, through pleiotropic effects, may prevent or reverse the endothelial dysfunction associated with LVH. Methods: After performing a banding of the ascending aorta for 2 months leading to the development of LVH, groups have been treated with atorvastatin 40 or 80 mg for 60 and 90 day periods. LVH was evaluated by echocardiographic studies. Vascular reactivity studies were performed in organ chambers. In vitro endothelial function was evaluated by plasmatic nitrites/nitrates, the degradations products of nitric oxide, and cGMP quantification. To quantify and qualify oxidative stress, protein carbonyl and angiotensin II levels were assessed. Results: Following 60 and 90 days of aortic banding, the development of LVH was observed in these groups. Concentration-response curves from rings of epicardial coronary arteries of groups treated with atorvastatin 40 and 80 mg for 30 and 60 days showed a significant decrease of endothelium-dependent relaxations with worsening of the endothelial dysfunction. Levels of cGMP were significantly decreased in the 60 days treated sham group and levels of ANG II were increased in the latter and also in the 90 days banded groups treated with 80 mg for 30 days compared to controls. The expression of protein carbonyl increased in the sham group treated with atorvastatin 80 mg compatible with an increase in oxidative stress. Conclusion: The administration of atorvastatin does not limit the development of LVH nor the endothelial dysfunction in our model. On the opposite, atorvastatin at a high dose has a toxic effect on epicardial coronary arteries by exacerbating the endothelial dysfunction.

Širdies ir kraujagyslių ligos (ŠKL) yra pagrindinė mirties priežastis visoje Europoje ir Lietuvoje. Literatūroje plačiai, tačiau nevienareikšmiai aptarta MS svarba širdies kraujagyslių ligų atsiradimui. Neatsakyta į vieną iš pagrindinių klausimų: kurie MS sudarantys rizikos veiksniai ar jų grupės daugiausia lemia širdies ir kraujagyslių ligų progresavimą. Mes savo darbe įvertinome arterijų funkcinių ir struktūrinių pokyčių bei kairiojo skilvelio miokardo masės indekso kitimų sąsajas su amžiumi, lytimi ir MS; taip pat atsižvelgėme ne tik į MS, bet ir į atskirų širdies bei kraujagyslių rizikos veiksnių nepriklausomą įtaką kardiovaskuliniam pažeidimui. Be to, bandėme nustatyti, koks MS sudarančių atskirų komponentų skaičius gali daugiausia lemti širdies ir kraujagyslių arterijų funkcinius ir struktūriniais kitimus bei kairiojo skilvelio miokardo masės didėjimą. Darbe nustatyta, kad sergantiesiems metaboliniu sindromu nepriklausomai nuo lyties ir amžiaus yra didesnis intimos medijos storis, šlaunies miego arterijų pulsinės bangos greitis ir kairiojo skilvelio miokardo masės indeksas. Didesnis miego arterijoje aterosklerozinių plokštelių skaičius rastas tik moterims su metaboliniu sindromu. Širdies ir kraujagyslių pažeidimų rizika sergantiems metaboliniu sindromu vyrams ir moterims taip pat buvo skirtinga. Vyrams su MS aptikta 2,14 karto didesnė kairiojo skilvelio hipertrofijos ir 4,9 karto – intimos medijos sustorėjimo tikimybė. Moterims metabolinis sindromas nesukelė intimos... [to full text] / Cardiovascular diseases (CVD) are the main cause of death all over the Europe and were the most prevalent disease in Lithuania in 2010. Based on some of the data, MS risk factors have different influence on changes of artery structure and function. MS and its components can influence differently the emergence of cardiovascular diseases and advance of complications in men and women. Furthermore, we tried to estimate the number of separate components constituting MS that can have the most significant influence on functional and structural changes in cardiovascular arteries and increase of the left ventricle myocardial mass index. The particularity of changes in different arterial stiffness indicators in patients with MS has not been determined yet in the literature, as well as prognostic value of MS when initiating early disorders in arterial structure and function and left ventricular hypertrophy. The research showed the following results: in subjects with metabolic syndrome irrespectively their gender and age higher intima-media thickness, femoral-carotid arteries pulse wave velocity and left ventricular myocardial mass index were found. However, higher number of atherosclerotic plaques in carotid artery was found only in females. Risk of cardiovascular disorders in males and females with metabolic syndrome is different. Nor in males, neither in females metabolic syndrome had no direct influence on pulse wave velocity, intima-media thickness, hypertrophy of left ventricle... [toliau žr. visą tekstą]

Širdies ir kraujagyslių ligos (ŠKL) yra pagrindinė mirties priežastis visoje Europoje ir Lietuvoje. Literatūroje plačiai, tačiau nevienareikšmiai aptarta MS svarba širdies kraujagyslių ligų atsiradimui. Neatsakyta į vieną iš pagrindinių klausimų: kurie MS sudarantys rizikos veiksniai ar jų grupės daugiausia lemia širdies ir kraujagyslių ligų progresavimą. Mes savo darbe įvertinome arterijų funkcinių ir struktūrinių pokyčių bei kairiojo skilvelio miokardo masės indekso kitimų sąsajas su amžiumi, lytimi ir MS; taip pat atsižvelgėme ne tik į MS, bet ir į atskirų širdies bei kraujagyslių rizikos veiksnių nepriklausomą įtaką kardiovaskuliniam pažeidimui. Be to, bandėme nustatyti, koks MS sudarančių atskirų komponentų skaičius gali daugiausia lemti širdies ir kraujagyslių arterijų funkcinius ir struktūriniais kitimus bei kairiojo skilvelio miokardo masės didėjimą. Darbe nustatyta, kad sergantiesiems metaboliniu sindromu nepriklausomai nuo lyties ir amžiaus yra didesnis intimos medijos storis, šlaunies miego arterijų pulsinės bangos greitis ir kairiojo skilvelio miokardo masės indeksas. Didesnis miego arterijoje aterosklerozinių plokštelių skaičius rastas tik moterims su metaboliniu sindromu. Širdies ir kraujagyslių pažeidimų rizika sergantiems metaboliniu sindromu vyrams ir moterims taip pat buvo skirtinga. Vyrams su MS aptikta 2,14 karto didesnė kairiojo skilvelio hipertrofijos ir 4,9 karto – intimos medijos sustorėjimo tikimybė. Moterims metabolinis sindromas nesukelė intimos... [toliau žr. visą tekstą] / Cardiovascular diseases (CVD) are the main cause of death all over the Europe and were the most prevalent disease in Lithuania in 2010. Based on some of the data, MS risk factors have different influence on changes of artery structure and function. MS and its components can influence differently the emergence of cardiovascular diseases and advance of complications in men and women. Furthermore, we tried to estimate the number of separate components constituting MS that can have the most significant influence on functional and structural changes in cardiovascular arteries and increase of the left ventricle myocardial mass index. The particularity of changes in different arterial stiffness indicators in patients with MS has not been determined yet in the literature, as well as prognostic value of MS when initiating early disorders in arterial structure and function and left ventricular hypertrophy. The research showed the following results: in subjects with metabolic syndrome irrespectively their gender and age higher intima-media thickness, femoral-carotid arteries pulse wave velocity and left ventricular myocardial mass index were found. However, higher number of atherosclerotic plaques in carotid artery was found only in females. Risk of cardiovascular disorders in males and females with metabolic syndrome is different. Nor in males, neither in females metabolic syndrome had no direct influence on pulse wave velocity, intima-media thickness, hypertrophy of left ventricle... [to full text]

Effet positif de la N-acétylcystéine sur la dysfonction endothéliale des artères coronaires épicardiques associée à une hypertrophie ventriculaire gauche dans un modèle porcin A. A. HORN, M-C AUBIN, YF SHI, J-C TARDIF, M. CARRIER , L. P. PERRAULT INSTITUT DE CARDIOLOGIE DE MONTRÉAL, MONTRÉAL, CANADA, Objectif : Il a été démontré dans le laboratoire que dans notre modèle d’hypertrophie ventriculaire gauche, la dysfonction endothéliale est secondaire à une diminution de la biodisponibilité du NO, celle-ci étant causée par une augmentation du stress oxydant tel que démontré par Malo et al. (2003) et Aubin et al. (2006). Le but de la présente étude est d’étudier l’effet d’un traitement chronique de la N-acétylcystéine (NAC) (un antioxydant) sur la dysfonction endothéliale associée à une hypertrophie ventriculaire gauche (HVG). Méthodologie: L’HVG a été induite par cerclage aortique (CA) chez vingt-et-un porcelets âgés de deux mois qui furent divisés aléatoirement en quatre groupes expérimentaux. Le groupe témoin (groupe 1) a été soumis à une thoracotomie antérolatérale gauche sans cerclage aortique (n=3). Le groupe 2 a été soumis à un cerclage aortique pour une période de 60 jours (n=6). Le groupe 3 a subi un cerclage aortique et a reçu un traitement oral de N-acétylcystéine de 1000 mg/jour per os pendant 60 jours commençant le jour de la chirurgie (n=6). Le groupe 4 a été soumis à un cerclage aortique et a reçu un traitement oral de N-acétylcystéine : 1000 mg/par jour pendant 30 jours commençant le jour 30 (post-chirurgie) (n=6). L’hypertrophie fut évaluée par échocardiographie. La réactivité vasculaire fut étudiée à l’aide de chambres d’organes par la construction des courbes concentration-réponse à la sérotonine (5-HT: relaxations induites par les récepteurs 5-HT1D, couplés aux protéines Gi) et à la bradykinine (BK: relaxations induites par les récepteurs B2, couplés aux protéines Gq). Les quantités de nitrites/nitrates et la production basale de GMPc ont été mesurées pour évaluer la fonction endothéliale. Le stress oxydant a été étudié en quantifiant les concentrations plasmatiques d’hydroperoxydes lipidiques et de glutathion réduit, ainsi que l’activité plasmatique des enzymes antioxydantes peroxydase du glutathion et dismutase du superoxyde. Résultats: Le rapport masse ventricule gauche/masse corporelle était significativement plus élevé pour le groupe 2 comparativement au groupe 1 (p<0,05) confirmant la présence d’une HVG. Le développement de l’HVG dans le groupe 3 a pu être prévenu par la NAC et sa progression fut atténuée dans le groupe 4 (p<0,05 versus groupe 2). La présence de la dysfonction endothéliale a été confirmée chez le groupe 2, tel qu’illustré par une diminution significative des relaxations maximales à la 5-HT et à la BK comparativement au groupe témoin. Le traitement à la NAC a significativement potentialisé les relaxations maximales (p<0,05) induites par la sérotonine et par la bradykinine, chez les deux groupes traités. Cette amélioration des relaxations dépendantes de l’endothélium peut être la conséquence d’une augmentation significative (p<0,05) de la biodisponibilité du monoxyde d’azote pour les cellules musculaires lisses, tel que suggéré par l’augmentation du ratio nitrites/nitrates et de la production basale de GMPc chez les groupes 3 et 4 comparativement au groupe 2. Cette augmentation du facteur relaxant peut résulter d’une augmentation de sa production par les cellules endothéliales ou d’une diminution de sa neutralisation par les espèces réactives oxygénées. De fait, les concentrations d’hydroperoxydes lipidiques étaient significativement inférieures (p<0,05) et associées à une augmentation des concentrations de l’antioxydant glutathion réduit et de l’activité de la peroxydase du glutathion chez les deux groupes traités par rapport au groupe 2. Conclusion: Le traitement à la NAC prévient le développement de la dysfonction endothéliale coronaire ainsi que l’HVG qui lui est associée. / Beneficial effect of N-acetylcysteine on endothelial dysfunction of epicardial coronary arteries associated with left ventricular hypertrophy in a porcine model A.A. HORN, M-C AUBIN, YF SHI, J-C TARDIF, M. CARRIER , L. P. PERRAULT MONTREAL HEART INSTITUTE, MONTREAL, CANADA Objective : In our left ventricular hypertrophy (LVH) model, endothelial dysfunction is secondary to a reduced bioavailability of NO caused by increased oxidative stress demonstrated by Malo and al. (2003) and Aubin and al. (2006). The aim of this study was to investigate the potential effect of chronic administration of N-acetylcysteine (NAC), a thiol drug with antioxidant properties, on the coronary endothelial dysfunction associated with LVH. Design and method: LVH was induced by aortic banding (AB) on swine for a two-month period. Twenty-one 8-week-old Landrace male swine were randomly divided into 4 experimental groups. The sham group (group 1) was submitted to a thoracotomy without aortic banding (AB). The untreated aortic banded group (group 2) was kept for 60 days. The first AB treated group (group 3) received 1000mg/day of NAC per os for 60 days starting on the day of the surgery. The second AB treated group (group 4) received the same oral dose of NAC for 30 days starting on day 30. Hypertrophy was assessed by echocardiography. Coronary vascular reactivity was evaluated in organ chambers, by the construction of concentration-response curves to serotonin (5-HT: relaxations mediated by 5-HT1D receptors, coupled to Gi proteins) and bradykinin (BK: relaxations mediated by B2 receptors, coupled to Gq proteins). Levels of nitrite/nitrate and basal cGMP levels were measured to evaluate endothelial dysfunction. Finally, to assess oxidative stress, plasma lipid hydroperoxide levels (LPO), reduced glutathione as well as the activity of antioxidant enzymes glutathione peroxidase and superoxide dismutase were measured. Results: The LV mass/ body weight ratio was significantly higher in group 2 compared to group 1 confirming the development of LVH (p<0.05). The latter was found to be associated with a significant endothelial dysfunction. NAC did prevent LVH development in group 3 and attenuated its progression in group 4 (p<0.05). Concentration response curves to NAC showed improvement in endothelium-dependent relaxations to serotonin and to bradykinin (p<0.05). NAC treatment markedly improved maximal relaxations mediated by serotonin and bradykinin in both treated groups (p<0.05). The observed improvement in endothelium-dependent relaxations was supported by the increase of the bioavailability of NO for smooth muscle cells as suggested by the increase of the nitrite/nitrate ratio and the basal production of cGMP in groups 3 and 4 in comparison to group 2 (p<0.05). The increase of this relaxing factor could result from an increase of its production by endothelial cells or by a decrease of its neutralization by reactive oxygenated species. The lowering of LPO levels was accompanied by a higher glutathione concentration and glutathione peroxidase activity in both NAC treated groups compared to group 2 (p<0.05). Conclusions: NAC treatment demonstrated potent antioxidant properties in this porcine LVH model by slowing LVH development and restoring coronary endothelium-dependent relaxations.