Left ventricular hypertrophy (LVH) and increases in large artery stiffness predict cardiovascular outcomes in patients with renal failure. What determines left ventricular mass index (LVMI) and large artery stiffness and the contribution toward LVH and large artery dysfunction is not entirely clear. Consequently, this cross sectional study was aimed at assessing the various factors impacting on LVH in haemodialysis (HD), to contribute toward our understanding of the pathophysiology of LVH and large artery dysfunction in 94 adult HD patients. Pre- and post-dialysis blood pressures (BPs) were determined over 12 sessions of dialysis and averaged. Pulse wave analysis performed at the carotid, femoral and radial arteries was employed to determine pulse wave velocity (PWV) and central augmentation index (AIc). Echocardiography was performed to determine left ventricular mass (LVM) indexed to body surface area (LVMI). Natriuretic peptides, procollagen type I c-peptide (PIP), c-terminal telopeptide of type I collagen (ICTP), matrix metalloproteinases and their inhibitors were studied. The prevalence of LVH was 72.8 % (67/92) .On multivariate analysis pre- (p≤ 0.005), post- (p<0.05) and averaged dialysis (p < 0.015) systolic BP were associated with LVMI and PWV. 24 hour (r = 0.260, p = 0.026), day (r = 0.247, p = 0.036), and night (r= 0.241, p = 0.042) systolic BP were not more closely associated with LVMI than the averaged dialysis systolic BP (r = 0.272, p = 0.010). Similarly 24 hour (r = 0.41, p = 0.0003), day (r=0.400, p = 0.0005), and night (r =0.416, p = 0.0003) systolic BP were not more closely associated with PWV than the post-dialysis systolic BP (r=0.39, p=0.0001) indicating that these BP measurements are as effective as 24-hour ambulatory BP in predicting cardiovascular target organ changes. No relationship between either PWV (r=-0.08), or AIc (r=-0.10) and LVMI, between PWV (r=-0.11), or AIc (r=0.03) and LV MWT was noted. IVCD was independently associated with LVMI (partial r adjusted for average dialysis SBP=0.27, p=0.014; partial r adjusted for 24-hour SBP=0.29, p=0.013), and LV mean wall thickness (p<0.01), but not with LV relative wall thickness (p=0.18), or LV end diastolic diameter (p=0.88). An association between IVCD and AIc (partial r adjusted for average dialysis SBP=0.21, p<0.05), but not PWV was noted. NT-proANP and NT-proBNP were independently associated with LVMI (p<0.0001) but neither were associated with IVCD independent of LVMI suggesting a close association with LVMI in HD. Serum concentrations of matrix metalloproteinases 1, 2 and 9, and their tissue inhibitors (1 and 2) were not associated with LVMI, remodelling or PWV and neither procollagen I nor the C-terminal telopeptide of type I collagen (ICTP) were associated with LVMI. Thus, factors impacting on LVH in this study were systolic BP, NT-proANP, NT-proBNP and IVCD.

O objetivo do estudo foi verificar os efeitos da redução parcial do treinamento de força (TF) sobre o desempenho de força dinâmica máxima (1RM), de potência e do salto vertical (SV) e sobre a área de secção transversa muscular (ASTM) dos membros superiores (MMSS) e inferiores (MMII) em indivíduos fisicamente ativos. Para isso, 33 sujeitos do sexo masculino, sem experiência em TF, foram recrutados e divididos randomicamente nos grupos: treinamento de força reduzido 1 (i.e. 2 séries x 8-6RM; 2x/semana) (TFR1), treinamento de força reduzido 2 (i.e. 4 séries x 8-6RM; 1x/semana) (TFR2) e destreinamento (DE). Inicialmente, todos efetuaram oito semanas de TF (3-4 séries, 15-6RM e 2-3x/semana). Posteriormente, os grupos TFR1 e TFR2 efetuaram oito semanas de TF com reduções no volume das sessões e/ou na frequência semanal, enquanto o grupo DE interrompeu completamente o TF. O modelo misto de análise de variância foi utilizado para testar as alterações no desempenho de 1RM, potência e SV e na ASTM de MMII e MMSS nos grupos TRF1, TFR2 e DE nas condições pré, pós-TF e pós-TFR. Ao término do período de TF, foram observados aumentos significantes de 27,9%, 26,7% e 28,4% na 1RM de MMII e de 37,2%, 38,2% e 41,8% na 1RM de MMSS nos grupos TFR1, TFR2 e DE, respectivamente. A potência de MMII aumentou 12,4%, 12,1% e 11,11%, e a de MMSS aumentou 15,8%, 15,3% e 19,3% nos grupos TFR1, TFR2 e DE, respectivamente. O salto vertical apresentou melhoras de 4,5%, 4,8% e 4,2% nos grupos TFR1, TFR2 e DE respectivamente; e a ASTM dos MMII e MMSS aumentou 6,9%, 6,1% e 5,8%; e 7,1%, 8,8% e 8,1%, respectivamente, nos grupos TFR1, TFR2 e DE. Após o período de TFR, foram observados comportamentos similares entre os grupos TFR1 e TFR2 com a manutenção dos resultados pós-TF. Por outro lado, o grupo DE apresentou quedas significantes de 17,1% e 23,5% no desempenho da 1RM e de 20,6% e 15,7% na potência de MMII e MMSS, respectivamente. O desempenho do salto vertical diminuiu em 4% e foram observadas reduções de 4,7% e 5,7% na ASTM de MMII e MMSS. Desta forma podemos concluir que um período de TFR promove manutenção no desempenho da força dinâmica máxima, da potência e do salto vertical e da massa muscular dos segmentos corporais independente do modelo de TRF utilizado / The aim of the present study was to evaluate the effect of two different reduced strength training programs on maximum dynamic strength (1RM), muscle power, and vertical jump (VJ) performance, and the maintenance of upper and lower limbs muscle mass (CSA). Thirty three young, physically active males, with no previous experience in strength training were randomly divided into three groups: reduced strength training 1 (i.e. 2 series x 8-6RM; 2x/week) (i.e. RST1), reduced strength training 2 (i.e. 4 series x 8-6RM; 1x/week) (i.e. RST2), and detraining (i.e. DE). Initially, all groups were submitted to 8 weeks of strength training (ST, 3-5 series, 15-6RM, 2-3x/week). After ST, groups RST1 and RST2 performed 8 weeks of reduced strength training, with changes in session volume and training frequency, while DE group stopped training. Mixed models analysis was used to compare 1RM, muscle power, VJ and CSA changes between groups and pre-ST, post-ST and post-RST. After 8 weeks of ST, we found significant increases of 27,9%, 26,7% and 28,4% in lower limbs 1RM and increases of 37,2%, 38,2% e 41,8% in upper limbs 1RM for RST1, RST2, and DE groups, respectively. We also found increases of 12,4%, 12,1% and 11,11% and 15,8%, 15,3% and 19,3% for lower and upper limbs power, respectively, for RST1, RST2, and DE groups. Vertical jump performance improved 4,5%, 4,8% and 4,2% for RST1, RST2, and DE groups, respectively; while lower and upper limbs CSA increased 6,9%, 6,1%, and 5,8%; and 7,1%, 8,8%, and 8,1%, respectively, for RST1, RST2, and DE groups. After the RST period, both RST1 and RST2 groups presented similar results when compared to the 8-week ST. However, the DE group showed significant decreases in lower (17,11%) and upper limbs (23,5%) 1RM; in lower (20,6%) and upper limbs (15,7%) muscle power; and in vertical jump performance (4%). Muscle cross sectional area was also reduced in lower (4,7%) and upper (5,7%) limbs after 8 weeks of DE. In conclusion, a RST period can promote maintenance of maximum dynamic strength, muscle power and vertical jump performance, and muscle mass independent of the training strategy

Cardiac hypertrophy defines an adaptive process brought about in response to sustained increases in haemodynamic work. Cardiomyocytes undergo an initial compensatory phase in which enlargement and contractility alterations normalise wall stress and maintain adequate perfusion of organs. In pathological hypertrophy, this deteriorates to a decompensated state characterised by ventricular dysfunction and predisposition to heart failure. In contrast, physiological hypertrophy and associated enhanced cardiac functioning arising from chronic exercise training does not progress to heart failure. Determination of the molecular pathways underlying myocardial hypertrophy remains a challenge for cardiovascular research. The objective of the work presented in this thesis was to identify genes differentially expressed during pathological and physiological hypertrophy in order to enhance our knowledge of the mechanistic processes involved. A reverse Northern hybridisation method was applied to profile the expression of specifically selected genes in the hypertrophic models examined. Functional categories represented in the gene panel assembled included cardiac contractile and cytoskeletal markers, matrix metalloproteinases, vasoactive pathway factors, calcium handling genes, ion channels, cardiac regulatory factors, signalling pathway intermediates, apoptotic factors and histone deacetylases. In order to investigate pathological hypertrophy, a deoxycorticosterone acetate-salt (DOCA-salt) rat model was utilised. DOCA-salt treated rats used in this study demonstrated a 1.4-fold increase in heart weight to body weight ratio compared to controls. Impaired cardiac function indicative of a decompensated pathological phenotype in the DOCA-salt treated group was demonstrated by way of decreased chamber size, impaired myocardial compliance and significantly reduced cardiac output. Reverse Northern hybridisation analysis of 95 selected genes identified a number of candidates with differential expression in hearts of DOCA-salt treated rats. Increased gene expression was demonstrated for the collagenase MMP1 and stress-activated signal transduction factor Sin1. In contrast, the sarcoplasmic reticulum calcium ATPase SERCA-2 and anti-apoptotic factor BCL2l-10 genes exhibited decreased expression. To investigate changes in gene expression associated with physiological hypertrophy, use was made of an endurance run-trained rat model. The run-trained rats used in this study demonstrated a 24.1% increase in heart weight to body weight ratio and improvements in performance consistent with physiological cardiac adaptation. These performance indicators included improvements in systolic volume, cardiac output, myocardial compliance and bio-energetic function. Reverse Northern hybridisation expression analysis of 56 genes identified a number of differentially expressed mRNA transcripts in run-trained hypertrophied hearts. Four genes shown to demonstrate reduced expression in the run-trained rat model were interleukin-1 receptor associated kinase (IRAK1) and the developmentally expressed transcription factors Nkx-2.3, dHAND, and IRX-2. Based upon the reverse Northern hybridisation results, four genes were selected for Western blotting analysis of rat cardiac tissue. Of these, MMP1 and a putative isoform of Sin1 exhibited increased levels in DOCA-salt treated hypertrophic left ventricular tissue, results that correlate with the findings of increased mRNA expression for these two genes. Therefore, this study identified MMP1 and Sin1 as candidates involved in pathological but not physiological hypertrophy. This finding is in accord with other recent investigations demonstrating that pathological hypertrophy and physiological hypertrophy are associated with distinct molecular phenotypes. An aside to the major objective of identifying genes differentially regulated in left ventricular hypertrophy involved the application of the P19CL6 cell in vitro model of cardiomyogenesis to compare protein expression during hypertrophy and development. The Sin1 isoform, found to be up-regulated during DOCA-salt induced hypertrophy, was also shown to be more abundant in differentiating, than non-differentiating, P19CL6 cells. This result is consistent with the developing paradigm that implicates 'fetal' genes in the hypertrophic remodelling process.

Left ventricular hypertrophy (LVH) in response to pressure overload is associated with increased cardiovascular morbidity and mortality, making its prevention an important therapeutic goal. The role of a calcineurin-dependent molecular pathway in the induction of pressure-overload LVH is controversial. The present study tested the hypothesis that, in the setting of LV pressure overload, activation of the systemic renin-angiotensin system was necessary for activation of this calcineurin pathway. Mild LV pressure overload was induced in male Wistar rats by abdominal aortic constriction (AAC) or transverse aortic arch constriction (TAC), producing well-matched pressure gradients of 37 ?? 8 and 35 ?? 15 mmHg, respectively. Tight transverse aortic arch constriction (TTAC) in additional animals produced a pressure gradient of 75 ?? 15 mmHg. Only AAC increased plasma renin concentration and activated the calcineurin pathway, indicated by increased nuclear NFAT3 content. Plasma renin concentration and nuclear NFAT3 content were unchanged in TAC and TTAC animals. AAC animals developed more LVH 21 days post-banding than TAC and TTAC animals: the slope of the relationship between LV/body weight ratio and systolic blood pressure was much steeper in AAC animals than the combined TAC and TTAC animals (20x10-6 versus 5x10-6, p<0.001). Treatment with the calcineurin inhibitor FK506 did not significantly alter the slope of this relationship in the combined TAC and TTAC animals (8x10-6), but FK506 abolished this relationship in AAC animals (-5x10-6, R =0.0003). These data indicate that activation of the calcineurin pathway occurs only in high-renin hypertension, providing an additional stimulus to LVH induction. Calcineurin plays no role in the induction of LVH in low-renin hypertension, which is much more common clinically.

The right ventricle (RV) of the heart is clearly an extremely important component of cardiovascular function and physiology. The RV is affected in many cardiovascular disease processes, including pulmonary arterial hypertension (PAH), congenital heart disease, and left ventricular failure. In PAH, the performance of the RV is the strongest predictor of morbidity and mortality. Several advances in PAH therapies have occurred over the past decade, including the use of phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists (ETRAs), and experimental metabolic modulators (Dichloroacetate-DCA). Most therapies for PAH are focused on decreasing RV afterload by vasodilation of the pulmonary vasculature, though there is a surprising lack of focus on direct effects of therapies on the RV. In PAH, the RV compensates to the increase in afterload by hypertrophy, this hypertrophic defense mechanism eventual falls short and the RV progresses to failure and patient death. The specific aims of our investigations are to assess the effects of PAH therapies on RV in normal and hypertrophied states, as seen in PAH. We utilize human RV samples attained from cardiac surgical procedures to perform in-vitro analysis of protein and mRNA expression of the targets of PAH therapies. We also use a rat model of PAH and subsequent RV hypertrophy to verify human data and to also perform applied physiology experiments to isolate ex-vivo effects of PAH therapies on the RV. The experiments and data gathered in this thesis represent the insight into the importance of the RV in PAH therapies and how these therapies directly mediate the state of inotropy of the RV. A conclusion of greater importance is the better understanding of RV-specific changes in gene expression when the RV undergoes hypertrophy. By demonstrating the up-regulation of protein expression in RVH we are able to potentially tailor therapies to only improve performance of the diseased RV, while sparing the LV if it is otherwise normal. This is a true shift in paradigm as all current cardiac therapeutics effect both right and left ventricle. / Experimental Medicine

Free weights are generally preferred over machines by practitioners of strength training because they involve incorporation of greater muscle mass because of the greater stabilization that is required. Using free weights may therefore allow one to gain more muscle mass and strength with chronic training; however, this has not been thoroughly addressed. The purpose of this study was to compare the effect of training with free weights or machines on muscle mass, testosterone and cortisol concentrations, and strength. Fifteen males and twenty-one females aged 22 ± 3 y with previous weight training experience trained using only free weights or only machines for eight weeks. Hormone concentrations were assessed via saliva samples pre and post workout at the beginning, mid-way, and end of the study. Muscle thickness, lean tissue mass, and strength were measured at the beginning and the end of the study. Elbow flexor thickness increased significantly by 3.9% and a 5.1% in the free weight group and machine group, respectively (p<0.01), with no difference between groups. Knee extensor thickness increased significantly by 4.6% and a 4.9% in the free weight group and machine group, respectively (p<0.01), with no difference between groups. No significant changes occurred in the lean tissue mass during the eight week training period. The group x time interaction for machine bench press strength was close to significance (p=0.054) with the machine training group experiencing a greater increase in strength compared to the free weight training group (13.9% vs. 8.6%). Free weight bench press, free weight squat, and Smith machine squat strength increased significantly in both groups (11-19%; p<0.01) with no difference between groups. The males in the free-weight group had a 21.7% increase in testosterone from before to after acute training sessions (p<0.01); however, the acute increase in testosterone to cortisol ratio in males training with free weights did not differ from males training on machines. Results from this study indicate that training with free weights or machines result in similar increases in muscle mass and strength, and testosterone to cortisol ratio. Males training with free weights may benefit from a greater acute increase in testosterone levels during individual training sessions.

Cardiac hypertrophy is an adaptive response in which the heart grows to normalize output during times of increased demand. This increase in size originates from the growth of cardiomyocytes rather than cellular division. Many cellular modifications observed during hypertrophy are reminiscent of apoptosis; caspase proteases, traditionally known for their role in apoptosis, have recently been implicated in non-apoptotic settings including cardiac differentiation. Studies have reported caspase-3 inhibition limits the heart`s ability to undergo pathological hypertrophy in vivo. Data presented here indicate that inhibition of caspase-3 and caspase-8 minimizes hypertrophic growth in primary cardiomyocytes. Phenylephrine induced an increase in cell size, which was attenuated upon addition of caspase inhibitors. These data suggest these proteins may be involved in hypertrophic growth of cardiomyocytes. Furthermore, results suggest that increased caspase activity may not be directly responsible for this effect. Rather, subcellular localization of caspase proteases may contribute to the effects seen during hypertrophy.

Introduction: Cardiac hypertrophy is an adaptive response to increased myocardial workload that becomes maladaptive when hypertrophied hearts are exposed to an acute metabolic stress, such as ischemia/reperfusion. Acceleration of glycolysis occurs as part of the hypertrophic response and may be maladaptive because it enhances glycolytic metabolite accumulation and proton production. Activation of AMP-activated protein kinase (AMPK), a kinase involved in the regulation of energy metabolism, is proposed as a mechanism for the acceleration of glycolysis in hypertrophied hearts. However, this concept has not yet been proven conclusively. Additionally, several studies suggest that AMPK is involved in hypertrophic remodeling of the heart by influencing cardiac myocyte growth, a suggestion that remains controversial. Hypothesis: AMPK mediates hypertrophic remodeling in response to pressure overload. Specifically, AMPK activation is a cellular signal responsible for accelerated rates of glycolysis in hypertrophied hearts. Additionally, AMPK influences myocardial structural remodeling and gene expression by limiting hypertrophic growth. Experimental Approach: To test this hypothesis, H9c2 cells, derived from embryonic rat hearts, were treated with (1 µM) arginine vasopressin (AVP) to induce hypertrophy. Substrate utilization was measured and the effects of AMPK inhibition by either Compound C or by adenovirus-mediated transfer of dominant negative AMPK were determined. Subsequently, adenovirus-mediated transfer of constitutively active form of AMPK (CA-AMPK) was expressed in H9c2 to specifically increase AMPK activity and, thereby, further characterize the role of AMPK in hypertrophic remodeling. Results: AVP induced a metabolic profile in hypertrophied H9c2 cells similar to that in intact hypertrophied hearts. Glycolysis was accelerated and palmitate oxidation was reduced with no significant alteration in glucose oxidation. These changes were associated with AMPK activation, and inhibition of AMPK ameliorated but did not normalize the hypertrophy-associated increase in glycolysis. CA-AMPK stimulated both glycolysis and fatty acid oxidation, and also increased protein synthesis and content. Howver, CA-AMPK did not induce a pathological hypertrophic phenotype as assessed by atrial natriuretic peptide expression. Conclusion: Acceleration of glycolysis in AVP-treated hypertrophied heart muscle cells is partially dependent on AMPK. AMPK is a positive regulator of cell growth in these cells, but does not induce pathological hypertrophy when acting alone.

Free weights are generally preferred over machines by practitioners of strength training because they involve incorporation of greater muscle mass because of the greater stabilization that is required. Using free weights may therefore allow one to gain more muscle mass and strength with chronic training; however, this has not been thoroughly addressed. The purpose of this study was to compare the effect of training with free weights or machines on muscle mass, testosterone and cortisol concentrations, and strength. Fifteen males and twenty-one females aged 22 ± 3 y with previous weight training experience trained using only free weights or only machines for eight weeks. Hormone concentrations were assessed via saliva samples pre and post workout at the beginning, mid-way, and end of the study. Muscle thickness, lean tissue mass, and strength were measured at the beginning and the end of the study. Elbow flexor thickness increased significantly by 3.9% and a 5.1% in the free weight group and machine group, respectively (p<0.01), with no difference between groups. Knee extensor thickness increased significantly by 4.6% and a 4.9% in the free weight group and machine group, respectively (p<0.01), with no difference between groups. No significant changes occurred in the lean tissue mass during the eight week training period. The group x time interaction for machine bench press strength was close to significance (p=0.054) with the machine training group experiencing a greater increase in strength compared to the free weight training group (13.9% vs. 8.6%). Free weight bench press, free weight squat, and Smith machine squat strength increased significantly in both groups (11-19%; p<0.01) with no difference between groups. The males in the free-weight group had a 21.7% increase in testosterone from before to after acute training sessions (p<0.01); however, the acute increase in testosterone to cortisol ratio in males training with free weights did not differ from males training on machines. Results from this study indicate that training with free weights or machines result in similar increases in muscle mass and strength, and testosterone to cortisol ratio. Males training with free weights may benefit from a greater acute increase in testosterone levels during individual training sessions.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences