Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

Impaired endothelial vasomotor function is a hallmark of many chronic disease states, including essential hypertension and type 2 diabetes mellitus. Loss of the homeostatic role of the endothelium in large conduit arteries can contribute to the pathogenesis of cardiovascular conditions in these vessels (e.g. stroke, atherosclerosis). A fundamental understanding of mechanisms controlling endothelial function in hypertension and type 2 diabetes mellitus is required for appropriate clinical strategies targeting the cardiovascular conditions associated with these diseases. The vast majority of basic science studies examining endothelial function in animal models of hypertension and type 2 diabetes have been conducted in males. Studying endothelial function in females is imperative for determining potential sex-specific mechanisms of dysfunction and thus appropriate therapeutic strategies. Thus the global purpose of this thesis is to identify and characterize the pathways controlling impaired vasomotor function in female animal models of two chronic disease states: hypertension and type 2 diabetes mellitus. Chapters 2 and 3 of this thesis examine sex differences in endothelium-dependent vasorelaxation (EDR) and vasocontraction (EDC) of aortic segments isolated from male and female spontaneously hypertensive rats (SHR), a model of essential hypertension, as the animals age between 16 and 30 wk old. All endothelial vasomotor data presented in the Abstract are peak responses to 10⁻⁵ M acetylcholine. Endothelial vasomotor impairment is represented by lower EDR or by higher EDC. These present data confirmed well-established findings from the literature that 16 wk old male SHR exhibit endothelial vasomotor impairments (EDR: 77±4 %; EDC: 76±7 %) compared to normotensive Wistar-Kyoto (WKY; EDR: 89±6 %; EDC: 59±8 %; p<0.05) controls, and that this impairment worsens with ageing in 30 wk male SHR (EDR: 63±2 %; EDC: 91±3 %; p<0.05). The observation that EDR was reduced in 30 wk female SHR (EDR: 76±4 %) compared to 16 wk counterparts (EDR: 101±2 %; p<0.05), however, was novel and interesting, as there were previously no reports of vasomotor responses in female SHR older than 19 wk. Moreover, the blunted EDR response of 30 wk female SHR approached the level of impairment exhibited by 30 wk male SHR (but was still slightly greater in females; p<0.05). The limited sex difference of the EDR within 30 wk SHR (males –13 % vs. females; p<0.05) contrasted that of 16 wk SHR (males –24 % vs. females; p<0.05), when the robust and unimpaired relaxation displayed by females was much greater than the significantly blunted response of males. Interestingly, endothelium-dependent contractions in quiescent rings were moderate and similar between 16 wk (EDC: 50±4 %) and 30 wk female SHR (EDC: 59±7 %; p=N/S) as compared to the greater contractions of males that were exacerbated with ageing (see above; p<0.05 both sex and ageing comparison). A major role has been established for the cyclooxygenase (COX)-1-thromboxane A₂/prostaglandin (TP) receptor pathway in the impaired endothelial vasomotor function of male SHR. Indeed, a similar mechanism appears to be responsible for the dysfunction observed in 30 wk female SHR in this thesis since robust endothelial function was restored in these animals with both antagonism of TP receptor (EDR: 111±2 %; EDC: 7±2 %; p<0.05) and preferential inhibition of COX-1 (EDR: 112±3 %; EDC: –5±3 %; p<0.05). In contrast, preferential inhibition of COX-2 only partially tempered endothelial impairments of 30 wk female SHR (EDR: 99±5 %; EDC: 27±3 %; p<0.05), suggesting that, similar to ageing male SHR, this isoform makes at most a secondary contribution to the dysfunction in 30 wk female SHR. Collectively, these data indicate that ageing female SHR exhibit a mechanism of endothelial impairment that is similar to that of male SHR and that is largely COX-1- and TP receptor-dependent. Chapter 4 examines the ability of chronic dietary administration of the n-3 polyunsaturated fatty acid (PUFA), docosahexaenoic acid (DHA, 22:6 n-3), to ameliorate endothelial vasomotor function in adult male SHR with established hypertension. The impaired endothelial function of aortic segments isolated from adult male SHR (EDR: 48±6 %) was not improved following 10–12 wk of DHA feeding (EDR: 45±5 %; p=N/S). This finding was unexpected since it has been shown in the literature that feeding other n-3 PUFAs improves vasomotor responses in younger SHR, in which hypertension and its associated consequences are still developing. This is the first report of the effects of n-3 PUFA on endothelial vasomotor responses in adult SHR with established hypertension. These data suggest that dietary DHA do not improve vasomotor function in adult SHR. Chapter 5 examines α₁ adrenergic contraction and EDR of aortic segments isolated from 14 wk old female Zucker diabetic fatty rats (ZDF), a genetic model of high fat diet-induced obesity and type 2 diabetes, and lean non-diabetic female Zucker Lean rats. Additionally, some ZDF received an 8 wk administration of anti-diabetic metformin drug therapy, aerobic exercise training, or a combination of the two. Maximal α₁ adrenergic contractions were over 2-fold higher in high fat-fed ZDF (1.69±0.16 g) compared to Lean (0.71±0.13 g; p<0.05). This elevation in ZDF was abolished by exercise training alone (1.02±0.17 g; p<0.05) but was not altered by metformin (1.56±0.19 g; p=N/S). In contrast to the severely impaired endothelial vasomotor function reported in male ZDF in the literature, robust EDR was observed in female ZDF (72±7 %) that was similar to Lean (75±6 %; p=N/S) and that was unaltered by exercise training (76±5 %; p=N/S) or metformin (76±6 %; p=N/S). These results indicate that enhanced α₁ adrenergic contraction is a mechanism of altered vasomotor function in female type 2 diabetic ZDF rats and that it could possibly be addressed by a chronic exercise training intervention. The main novelty of the thesis is the extension of the current understanding of endothelial vasomotor function to hypertensive and type 2 diabetic females. The knowledge gained from examining mechanisms involved in endothelial impairments in ageing hypertensive females and from testing the therapeutic potential of currently used anti-diabetic interventions in the type 2 diabetic female vasculature has interesting potential application. This basic scientific information could help direct clinical therapeutic strategies to target population-specific mechanisms of dysfunction. Understanding female sex-specific endothelial behaviour in patient populations is important for describing cardiovascular complications, defining mechanisms, and applying appropriate therapeutic targets. Findings from this thesis indicate a sex-dependence of the total divergence of endothelial function (e.g. female type 2 diabetic rats vs. male counterparts in the literature) and of the interaction of disease variables (e.g. age) and endothelial vasomotor responses.

Impaired endothelial vasomotor function is a hallmark of many chronic disease states, including essential hypertension and type 2 diabetes mellitus. Loss of the homeostatic role of the endothelium in large conduit arteries can contribute to the pathogenesis of cardiovascular conditions in these vessels (e.g. stroke, atherosclerosis). A fundamental understanding of mechanisms controlling endothelial function in hypertension and type 2 diabetes mellitus is required for appropriate clinical strategies targeting the cardiovascular conditions associated with these diseases. The vast majority of basic science studies examining endothelial function in animal models of hypertension and type 2 diabetes have been conducted in males. Studying endothelial function in females is imperative for determining potential sex-specific mechanisms of dysfunction and thus appropriate therapeutic strategies. Thus the global purpose of this thesis is to identify and characterize the pathways controlling impaired vasomotor function in female animal models of two chronic disease states: hypertension and type 2 diabetes mellitus. Chapters 2 and 3 of this thesis examine sex differences in endothelium-dependent vasorelaxation (EDR) and vasocontraction (EDC) of aortic segments isolated from male and female spontaneously hypertensive rats (SHR), a model of essential hypertension, as the animals age between 16 and 30 wk old. All endothelial vasomotor data presented in the Abstract are peak responses to 10⁻⁵ M acetylcholine. Endothelial vasomotor impairment is represented by lower EDR or by higher EDC. These present data confirmed well-established findings from the literature that 16 wk old male SHR exhibit endothelial vasomotor impairments (EDR: 77±4 %; EDC: 76±7 %) compared to normotensive Wistar-Kyoto (WKY; EDR: 89±6 %; EDC: 59±8 %; p<0.05) controls, and that this impairment worsens with ageing in 30 wk male SHR (EDR: 63±2 %; EDC: 91±3 %; p<0.05). The observation that EDR was reduced in 30 wk female SHR (EDR: 76±4 %) compared to 16 wk counterparts (EDR: 101±2 %; p<0.05), however, was novel and interesting, as there were previously no reports of vasomotor responses in female SHR older than 19 wk. Moreover, the blunted EDR response of 30 wk female SHR approached the level of impairment exhibited by 30 wk male SHR (but was still slightly greater in females; p<0.05). The limited sex difference of the EDR within 30 wk SHR (males –13 % vs. females; p<0.05) contrasted that of 16 wk SHR (males –24 % vs. females; p<0.05), when the robust and unimpaired relaxation displayed by females was much greater than the significantly blunted response of males. Interestingly, endothelium-dependent contractions in quiescent rings were moderate and similar between 16 wk (EDC: 50±4 %) and 30 wk female SHR (EDC: 59±7 %; p=N/S) as compared to the greater contractions of males that were exacerbated with ageing (see above; p<0.05 both sex and ageing comparison). A major role has been established for the cyclooxygenase (COX)-1-thromboxane A₂/prostaglandin (TP) receptor pathway in the impaired endothelial vasomotor function of male SHR. Indeed, a similar mechanism appears to be responsible for the dysfunction observed in 30 wk female SHR in this thesis since robust endothelial function was restored in these animals with both antagonism of TP receptor (EDR: 111±2 %; EDC: 7±2 %; p<0.05) and preferential inhibition of COX-1 (EDR: 112±3 %; EDC: –5±3 %; p<0.05). In contrast, preferential inhibition of COX-2 only partially tempered endothelial impairments of 30 wk female SHR (EDR: 99±5 %; EDC: 27±3 %; p<0.05), suggesting that, similar to ageing male SHR, this isoform makes at most a secondary contribution to the dysfunction in 30 wk female SHR. Collectively, these data indicate that ageing female SHR exhibit a mechanism of endothelial impairment that is similar to that of male SHR and that is largely COX-1- and TP receptor-dependent. Chapter 4 examines the ability of chronic dietary administration of the n-3 polyunsaturated fatty acid (PUFA), docosahexaenoic acid (DHA, 22:6 n-3), to ameliorate endothelial vasomotor function in adult male SHR with established hypertension. The impaired endothelial function of aortic segments isolated from adult male SHR (EDR: 48±6 %) was not improved following 10–12 wk of DHA feeding (EDR: 45±5 %; p=N/S). This finding was unexpected since it has been shown in the literature that feeding other n-3 PUFAs improves vasomotor responses in younger SHR, in which hypertension and its associated consequences are still developing. This is the first report of the effects of n-3 PUFA on endothelial vasomotor responses in adult SHR with established hypertension. These data suggest that dietary DHA do not improve vasomotor function in adult SHR. Chapter 5 examines α₁ adrenergic contraction and EDR of aortic segments isolated from 14 wk old female Zucker diabetic fatty rats (ZDF), a genetic model of high fat diet-induced obesity and type 2 diabetes, and lean non-diabetic female Zucker Lean rats. Additionally, some ZDF received an 8 wk administration of anti-diabetic metformin drug therapy, aerobic exercise training, or a combination of the two. Maximal α₁ adrenergic contractions were over 2-fold higher in high fat-fed ZDF (1.69±0.16 g) compared to Lean (0.71±0.13 g; p<0.05). This elevation in ZDF was abolished by exercise training alone (1.02±0.17 g; p<0.05) but was not altered by metformin (1.56±0.19 g; p=N/S). In contrast to the severely impaired endothelial vasomotor function reported in male ZDF in the literature, robust EDR was observed in female ZDF (72±7 %) that was similar to Lean (75±6 %; p=N/S) and that was unaltered by exercise training (76±5 %; p=N/S) or metformin (76±6 %; p=N/S). These results indicate that enhanced α₁ adrenergic contraction is a mechanism of altered vasomotor function in female type 2 diabetic ZDF rats and that it could possibly be addressed by a chronic exercise training intervention. The main novelty of the thesis is the extension of the current understanding of endothelial vasomotor function to hypertensive and type 2 diabetic females. The knowledge gained from examining mechanisms involved in endothelial impairments in ageing hypertensive females and from testing the therapeutic potential of currently used anti-diabetic interventions in the type 2 diabetic female vasculature has interesting potential application. This basic scientific information could help direct clinical therapeutic strategies to target population-specific mechanisms of dysfunction. Understanding female sex-specific endothelial behaviour in patient populations is important for describing cardiovascular complications, defining mechanisms, and applying appropriate therapeutic targets. Findings from this thesis indicate a sex-dependence of the total divergence of endothelial function (e.g. female type 2 diabetic rats vs. male counterparts in the literature) and of the interaction of disease variables (e.g. age) and endothelial vasomotor responses.

Les facteurs de risque des maladies cardiovasculaires, telle, que la détérioration du profil lipidique, deviennent plus prononcés après la ménopause, ce qui fait de la maladie coronarienne, l’une des principales causes de décès chez les femmes ménopausées. Une proportion importante de femmes prennent du poids après la ménopause en particulier dans la région abdominale entraînant par conséquent des perturbations métaboliques. Des données récentes suggèrent également que l’absence des œstrogènes observée à la ménopause favorise le développement de la stéatose hépatique. Cette dernière a été incriminée pour incriminée dans le développement de la résistance à l'insuline, et est de ce fait considérée comme une composante hépatique du syndrome métabolique. Il est impératif d'établir des stratégies visant à contrecarrer l'accumulation de graisse dans le foie et l’accroissement du tissu adipeux chez les femmes ménopausées, en tenant compte que l'utilisation de l'hormonothérapie substitutive est de nos jours moins soutenue. Les quatre études de la présente thèse ont été conduites pour tenter de fournir des informations sur le traitement et la prévention de l’augmentation de la masse graisseuse et de la stéatose hépatique qu’entraîne la suppression des œstrogènes, à travers les modifications du mode de vie (diète et exercice physique) chez la rate ovariectomizée (Ovx); un modèle animal de la ménopause. Dans les deux premières études nous nous sommes concentrés sur l’augmentation de la masse graisseuse et sa reprise suite à une perte de poids. Dans la première étude, nous avons montré que les rates Ovx qui ont suivi un programme de restriction alimentaire (FR) ont diminué significativement (P < 0.01) leur poids corporel, leur contenu en graisses intra-abdominales ainsi que leurs triacylglycérols (TAG) hépatiques, comparativement aux rates Ovx nourries à la diète normale. De plus, l’entraînement en résistance (RT) a prévenu la reprise de poids corporel ainsi que l’accroissement du tissu adipeux et l’accumulation de lipides dans le foie des rates Ovx, après l’arrêt du régime amaigrissant. Les résultats de la deuxième étude ont confirmé l'efficacité de la restriction alimentaire associée à l’entraînement en résistance (FR + RT) dans la réduction du poids corporel, des lipides dans le foie et le tissu adipeux chez les rates Ovx. Tenant compte des résultats de notre première étude, l’entraînement en résistance seulement a constitué un atout pour atténuer le poids corporel et la masse grasse reprise par les rates Ovx suite à un programme de perte de poids (FR + RT); bien que l'impact ait été moindre comparé au maintien seul de la restriction alimentaire. De la même manière que la supplémentation en œstrogènes, les résultats de la troisième étude indiquent que l'entraînement en endurance mené concurremment avec l’ovariectomie a significativement atténué l'accumulation de lipides dans le foie ainsi que dans le tissu adipeux. Toutefois, l’entraînement en endurance effectué avant l'ovariectomie n'a pas protégé contre l'accumulation des graisses qu’entraîne l'ovariectomie, si celui-ci est interrompu après l'ovariectomie. Enfin, pour compléter les résultats antérieurs, nous avons montré dans la quatrième étude que l’expression des gènes impliqués dans la synthèse de lipide; SREBP-1c, SCD-1, ChREBP, et ACC dans le foie a augmenté après le retrait des œstrogènes, tandis qu’une diminution (P < 0.01) des niveaux d'ARNm de PPAR-α a été observée. De plus, l'expression hépatique des gènes des cytokines pro-inflammatoires incluant IKKβ, IL-6 ainsi que le contenu protéinique de NF-кB étaient augmentés (P < 0.01) chez les rates Ovx par rapport aux rates ayant subi une Ovx simulée (Sham). Toutes ces perturbations ont été améliorées avec la supplémentation en œstrogènes seulement, ainsi qu'avec l'entraînement en endurance seulement. Dans l'ensemble, nos résultats indiquent que l'exercice physique (en résistance ou en endurance) a un impact significatif sur la réduction de l'accumulation des lipides dans le foie et dans le tissu adipeux des rates Ovx. De plus, chez les rates Ovx, l’entraînement en endurance mimerait les effets des œstrogènes sur l'expression des gènes impliqués dans l'accumulation de lipides et l’inflammation préclinique dans le foie. / Cardiovascular disease risk factors, such as lipid profile deterioration, become more pronounced after menopause making coronary heart disease a leading cause of death among postmenopausal women. A large proportion of women after menopause gain weight especially in the abdominal region resulting in several metabolic disturbances. Recent evidence also suggests that loss of estrogen function in menopause is associated with the development of a state of hepatic steatosis. Excessive fat accumulation in hepatocytes has been shown to play an important role in the development of insulin resistance and is even considered as a hepatic component of the metabolic syndrome. There is an important need to establish strategies to counteract fat accumulation in adipocyte and liver in postmenopausal women specifically considering the fact that utilization of hormone replacement therapy is now less supported. The four studies of the present thesis have been conducted in an attempt to provide information on the treatment and prevention of estrogen withdrawal-induced fat mass and hepatic steatosis via lifestyle modifications (diet and exercise training) in an ovariectomized (Ovx) rat model of menopause. In the first two studies we focused on fat mass gain and regain following weight loss. In study 1, we showed that food restriction program (FR) decreased (P < 0.01) body mass, intra-abdominal fat pad weight, and liver triacylglycerol (TAG) levels as compared to normally fed Ovx rats. Moreover, resistance training program (RT) was useful in preventing body weight as well as adipose tissue and liver fat regain in Ovx rats, following diet-induced weight loss. Results of study 2 confirmed the efficiency of the FR + RT program in reducing body weight as well as liver and adipocytes fat accretion in Ovx rats. In line with the findings of our first study, continuation of only RT constituted an asset to attenuate body weight and fat mass regain in Ovx rats following a FR + RT weight loss program, although the impact was less than maintaining FR alone. Similar to estrogen supplementation, results of study 3 indicated that endurance exercise training conducted concurrently with the induction of ovariectomy significantly attenuated liver and adipocyte fat accumulation. However, an endurance exercise training state acquired before ovariectomy did not provide any protective effects against ovariectomy-induced fat accumulation if exercise is discontinued after the ovariectomy. Finally, complementing previous findings we showed in study 4 that liver gene expressions of transcription factors SREBP-1c and ChREBP along with downstream lipogenic enzymes SCD-1 and ACC were increased with estrogens withdrawal conversely to reduced PPAR-α mRNA levels (P < 0.01). Furthermore, gene expressions of pro-inflammatory cytokines including IKKβ and IL-6 as well as protein content of NF-кB were higher (P < 0.01) in the liver of Ovx than in Sham animals. All of these responses were corrected with estrogen supplementation alone as well as with endurance exercise training alone in Ovx rats. On the whole, our results indicate that exercise training (resistance or endurance) has a significant impact on reducing fat accumulation in liver and adipocytes in Ovx rats. In addition, it seems that endurance exercise training in Ovx rats stimulates estrogenic-like effects on the expression of genes involved in lipid accumulation and sub-clinical inflammation in the liver.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

A presença de ventilação periódica durante o exercício confere pior prognóstico a pacientes com insuficiência cardíaca. Existem divergências quanto aos critérios para identificação deste fenômeno. Além disso, a interpretação dicotômica (presença ou ausência) quanto a este fenômeno dificulta a estratificação de risco mais detalhada dos pacientes com insuficiência cardíaca. Desta forma, esta tese avalia a utilização de técnicas estabelecidas para análise de variabilidade de sinais para quantificar as oscilações ventilatórias que ocorrem durante o teste cardiopulmonar de exercício, em indivíduos saudáveis, atletas e com insuficiência cardíaca. Um protocolo mais curto para realização de teste cardiopulmonar de exercício em cicloergômetro de braço foi proposto e validado. Tal protocolo foi utilizado em estudo posterior, onde se comprovou que, apesar dos tempos respiratórios não serem influenciados pelo tipo de exercício realizado, a variabilidade ventilatória é maior durante a realização de exercício dinâmico com membros superiores do que com membros inferiores. A capacidade aeróbica de indivíduos sadios também influencia a variabilidade ventilatória durante o teste cardiopulmonar de exercício. Isto foi comprovado pela menor variabilidade ventilatória no domínio do tempo em atletas do que sedentários durante exercício. A análise destes voluntários com o método da análise dos componentes principais revelou que em atletas a variabilidade do volume corrente é a principal responsável pela variabilidade da ventilação-minuto durante o exercício, ao passo que em sedentários a variabilidade da freqüência respiratória apresenta-se como principal responsável por tais variações. Em estudo randomizado e controlado comprovamos que, mesmo indivíduos sadios apresentam redução da variabilidade ventilatória ao exercício após 12 semanas de treinamento físico. Comprovamos que a reabilitação cardíaca reverteu a ocorrência de ventilação periódica em um paciente com insuficiência cardíaca e, finalmente, encontramos que a variabilidade ventilatória correlaciona-se inversamente com a fração de ejeção ventricular esquerda em pacientes com insuficiência cardíaca. Estudos futuros deverão analisar o poder prognóstico da variabilidade ventilatória nestes pacientes. / Exercise periodic breathing confers a bad prognosis in patients with heart failure. There is no agreement among proposed criteria to diagnose exercise periodic breathing. The dichotomic interpretation (presence or absence) when diagnosing this phenomenon impairs a more detailed risk stratification in heart failure. Thus, this thesis evaluates the use of established signal variability techniques to quantify ventilatory oscillations during cardiopulmonary exercise test, in healthy individuals, athletes and patients with heart failure. A short protocol used to perform cardiopulmonary exercise test in arm crank was proposes and validated. This protocol was used in the next study, which found that, although timing of breathing was not altered by exercise type, ventilatory variability was greater during arm dynamic exercise when compared to leg exercise. Aerobic capacity of healthy individuals also influences ventilatory variability during cardiopulmonary exercise test. This was proven by the lower time-domain ventilatory variability in athletes when compared to sedentary individuals. The evaluation of these individuals with principal components analysis showed that tidal volume variability is the principal component o minute-ventilation variability in athletes, whilst in sedentary men, respiratory frequency variability is the responsible for minute-ventilation variability. In a randomized controlled study we have found that even healthy individuals reduce their exercise ventilatory variability after 12 weeks exercise training. We have shown that cardiac rehabilitation reverted exercise periodical breathing in a patient with heart failure and, finally, found that exercise ventilatory variability inversely correlates to left ventricle ejection fraction in patients with heart failure. Future studies should evaluate the prognostic value of ventilatory variability in these patients.

A presença de ventilação periódica durante o exercício confere pior prognóstico a pacientes com insuficiência cardíaca. Existem divergências quanto aos critérios para identificação deste fenômeno. Além disso, a interpretação dicotômica (presença ou ausência) quanto a este fenômeno dificulta a estratificação de risco mais detalhada dos pacientes com insuficiência cardíaca. Desta forma, esta tese avalia a utilização de técnicas estabelecidas para análise de variabilidade de sinais para quantificar as oscilações ventilatórias que ocorrem durante o teste cardiopulmonar de exercício, em indivíduos saudáveis, atletas e com insuficiência cardíaca. Um protocolo mais curto para realização de teste cardiopulmonar de exercício em cicloergômetro de braço foi proposto e validado. Tal protocolo foi utilizado em estudo posterior, onde se comprovou que, apesar dos tempos respiratórios não serem influenciados pelo tipo de exercício realizado, a variabilidade ventilatória é maior durante a realização de exercício dinâmico com membros superiores do que com membros inferiores. A capacidade aeróbica de indivíduos sadios também influencia a variabilidade ventilatória durante o teste cardiopulmonar de exercício. Isto foi comprovado pela menor variabilidade ventilatória no domínio do tempo em atletas do que sedentários durante exercício. A análise destes voluntários com o método da análise dos componentes principais revelou que em atletas a variabilidade do volume corrente é a principal responsável pela variabilidade da ventilação-minuto durante o exercício, ao passo que em sedentários a variabilidade da freqüência respiratória apresenta-se como principal responsável por tais variações. Em estudo randomizado e controlado comprovamos que, mesmo indivíduos sadios apresentam redução da variabilidade ventilatória ao exercício após 12 semanas de treinamento físico. Comprovamos que a reabilitação cardíaca reverteu a ocorrência de ventilação periódica em um paciente com insuficiência cardíaca e, finalmente, encontramos que a variabilidade ventilatória correlaciona-se inversamente com a fração de ejeção ventricular esquerda em pacientes com insuficiência cardíaca. Estudos futuros deverão analisar o poder prognóstico da variabilidade ventilatória nestes pacientes. / Exercise periodic breathing confers a bad prognosis in patients with heart failure. There is no agreement among proposed criteria to diagnose exercise periodic breathing. The dichotomic interpretation (presence or absence) when diagnosing this phenomenon impairs a more detailed risk stratification in heart failure. Thus, this thesis evaluates the use of established signal variability techniques to quantify ventilatory oscillations during cardiopulmonary exercise test, in healthy individuals, athletes and patients with heart failure. A short protocol used to perform cardiopulmonary exercise test in arm crank was proposes and validated. This protocol was used in the next study, which found that, although timing of breathing was not altered by exercise type, ventilatory variability was greater during arm dynamic exercise when compared to leg exercise. Aerobic capacity of healthy individuals also influences ventilatory variability during cardiopulmonary exercise test. This was proven by the lower time-domain ventilatory variability in athletes when compared to sedentary individuals. The evaluation of these individuals with principal components analysis showed that tidal volume variability is the principal component o minute-ventilation variability in athletes, whilst in sedentary men, respiratory frequency variability is the responsible for minute-ventilation variability. In a randomized controlled study we have found that even healthy individuals reduce their exercise ventilatory variability after 12 weeks exercise training. We have shown that cardiac rehabilitation reverted exercise periodical breathing in a patient with heart failure and, finally, found that exercise ventilatory variability inversely correlates to left ventricle ejection fraction in patients with heart failure. Future studies should evaluate the prognostic value of ventilatory variability in these patients.

Selon les lignes directrices chez les patients coronariens, un programme d’entrainement aérobie doit combiner de l’entrainement continu à intensité modérée (ECIM) et par intervalles à haute intensité (EIHI), en étant progressif et structuré (périodisation linéaire [PL]), et manipulé selon les principes FITT qui incluent la fréquence, l’intensité, la durée, et la modalité (ou le type). Contrairement à la PL où la charge d’entrainement est constamment augmentée, la périodisation non-linéaire (PNL) de l’entrainement consiste à incorporer des périodes de récupération au cours d’un cycle d’entrainement afin d’optimiser les adaptations et d’éviter la monotonie et le surmenage. Chez les individus sains et atteints de maladie pulmonaire obstructive chronique, la PNL de l’entrainement aérobie a parfois montré des bénéfices supérieurs à la PL sur l’amélioration de l’endurance aérobie. Notre objectif principal était donc de comparer la PNL à la PL de l’entrainement aérobie sur la fonction cardiorespiratoire chez des patients coronariens. Nous avons ensuite comparé les adaptations cardiaques pour les deux types de périodisation au niveau du ventricule gauche (VG) dans une deuxième étude. Nous avions comme hypothèse que la PNL de l’entrainement aérobie apporterait davantage de gains sur les paramètres de réponses cardiopulmonaires à l’effort comparativement à la PL. Un total de 39 patients coronariens stables, recrutés à l’Institut de Cardiologie de Montréal entre 2016 et 2018, ont effectué une épreuve cardiopulmonaire à l’effort avec mesure des échanges gazeux, et une échocardiographie de repos avant et après une intervention d’entrainement. Les mesures de fonction cardiorespiratoire comprenaient la consommation d’oxygène au pic de l’exercice (V̇O2pic), la puissance aérobie maximale, la ventilation minute (V̇E), les variables d’effort sous-maximales (pente d’efficacité de la consommation d’oxygène PECO], pente de ventilation sur la production de dioxyde de carbone [V̇E/V̇CO2]), les consommations d’oxygène aux 1er [SV1] et 2e [SV2] seuils ventilatoires), et le pouls en oxygène (pouls en O2). Nous avons également mesuré la proportion de hauts et faibles répondeurs dans chacun des groupes selon la médiane du delta V̇O2pic. Les mesures d’échocardiographie comprenaient des mesures de la fonction systolique et diastolique, et des mesures de déformation de la paroi du VG. Les participants ont été répartis aléatoirement soit dans le groupe PL (n = 20, 65±10 ans), soit dans le groupe PNL (n = 19, 66±5 ans) pour 3 mois d’entrainement. L’entrainement consistait à 3 séances par semaine, pour les deux groupes, d’une durée de 30 à 60 minutes/séance, combinant de l’ECIM et de l’EIHI progressifs périodisés, ainsi que des exercices en résistance similaires non progressifs. Bien que les deux groupes étaient isoénergétiques (dépense énergétique totale équivalente sur 12 semaines), la dépense énergétique hebdomadaire était constamment augmentée dans le groupe PL, alors qu’elle était augmentée plus rapidement et entrecoupée d’une semaine d’entrainement à charge plus légère toutes les 4 semaines dans le groupe PNL. Nous avons observé une augmentation similaire du V̇O2pic, V̇E, PECO, VT1 et SV2, pouls en O2, de la fraction d’éjection du VG , la déformation radiale, et la vitesse de déformation radiale du VG (interaction tempsgroupe : p > 0,05 ; effet du temps : p < 0,05) entre les 2 groupes. La proportion de non, faibles et hauts répondeurs était similaire entre les 2 groupes (p = 0,29). Cependant, la fonction diastolique n’a pas évolué après les 12 semaines d’entrainement dans aucun des deux groupes. Nos résultats suggèrent que dans cette population, une variation accrue de la charge par la périodisation non-linéaire d’entrainement ne procure pas de gain additionnel dans la réponse cardiopulmonaire à l’effort et dans la fonction cardiaque de patients coronariens. Bien qu’il ne s’agisse pas d’une comparaison directe, une autre étude a rapporté une proportion de 37 % de hauts répondeurs auprès de 1171 patients coronariens après un programme d’entrainement non périodisé de 3 mois, comparativement à 60 et 47 % dans nos groupes PL et PNL, respectivement. Sachant que la non-réponse à l’entrainement est associée à une plus grande mortalité à long-terme, davantage d’études sont nécessaires afin de déterminer si la périodisation de l’entrainement (PL ou PNL) peut mener à une réponse à l’entrainement plus grande et être incorporée dans les programmes de réadaptation cardiaque. / Guidelines on exercise training in patients with coronary heart disease (CHD)suggest that an exercise training program with should combine moderate-intensity continuous (MICT) with a high-intensity interval (HIIT) training, with a constant progressive and structured increase of the training load (linear periodization [LP]) in the course of the program. As opposed to the LP, non-linear periodization (NLP) is characterized by greater increase of the training load intercepted by one training week with a lighter training load. NLP is used in athletes to bring variation in the training load, optimize training adaptation, avoid a plateau, monotony, and over-reaching. In healthy and individuals with chronic obstructive pulmonary disease, NLP showed greater improvement in aerobic endurance. Our main objective was to compare the NLP with the LP protocol on the cardiopulmonary exercise response in patients with CHD. Then, we compared the cardiac adaptation of the left ventricle (LV) between both aerobic training periodization. We hypothesized that NLP will be superior for improving cardiorespiratory parameters compared to LP. We recruited 39 patients with stable CHD from the Montreal Heart Institute, between 2016 and 2018. All completed a maximal cardiopulmonary exercise testing (CPET) with gas exchange measurements and a resting cardiac echography before and after the training intervention. The CPET measurements included peak oxygen uptake (peak V̇O2), oxygen uptake efficiency slope (OUES), minute ventilation (V̇E), ventilatory efficiency slope (V̇E/V̇CO2 slope), oxygen uptake at the first (VT1) and second (VT2) ventilatory thresholds, and oxygen pulse (O2pulse). We also assessed the proportion of non, low, and high responders between both aerobic training periodization using the median of the delta peak V̇O2. The cardiac function measurements included the systolic and the diastolic functions, and the myocardial strain and strain rates in the LV. Exercise training protocols included 3 sessions/week, for 30 to 60 minutes/session, combining a periodized HIIT and MICT, and a non-periodized resistance training. Weekly energy expenditure was constantly increased in the LP group for the aerobic training, while it was increased and intercepted with a lighter training load week each fourth week in the NLP group. VI We observed a similar improvement in both groups for peak V̇O2, OUES, VT1, VT2, O2pulse, 3-dimensional LV ejection fraction, radial strain and radial strain rates, (interaction time*group : p>0.05 ; time effect : p<0.05 with a superior effect size in the LP group). Proportion of high responders was similar between groups (p=0.29). Our results suggest that incorporating more training load variation does not bring more training adaptation in an exercise training program in patients with stable CHD. Despite it is not a direct comparison, another study showed a proportion of 37% of non-responders after a non-periodized training program in 1,171 patients with CHD, compared to 60 and 47% in the LP and NLP from our study, respectively. More studies are needed to examine if training periodization could lead to an increased training response and could be integrated in cardiac rehabilitation programs.