Chronic beta-adrenoreceptor activation increases cardiac cavity size through chamber remodeling and not via modifications in myocardial material properties

Chronic beta-adrenoreceptor (beta-AR) activation increases left ventricular (LV) cavity size by promoting a rightward shift in LV diastolic pressure-volume (P-V) relations in association with increases in low-tensile strength myocardial (non-cross-linked) collagen concentrations. Because diastolic P-V relations are determined by chamber remodeling as well as by myocardial material properties (indexed by myocardial stiffness), both of which are associated with modifications in myocardial collagen cross-linking, we evaluated whether chamber remodeling or alterations in myocardial material properties govern beta-AR-mediated modifications in diastolic P-V relations. The effects of chronic administration of isoproterenol (Iso; 0.04 mg.kg(-1).day(-1) from 12 to 19 mo of age) to spontaneously hypertensive rats (SHRs) on LV cavity dimensions, LV diastolic P-V relations, myocardial collagen characteristics, myocardial stiffness constants [e.g., the slope of the LV diastolic stress-strain relation (k)], and LV chamber and myocardial systolic function were assessed. SHRs at 19 mo of age had normal LV diastolic P-V relations, marked myocardial fibrosis (using a pathological score), increased myocardial cross-linked (insoluble to cyanogen bromide digestion) type I and type III collagen concentrations, and enhanced myocardial k values. Iso administration to SHRs resulted in enlarged LV cavity dimensions mediated by a rightward shift in LV diastolic P-V relations, increased volume intercept of the LV diastolic P-V relation, decreased LV relative wall thickness despite a tendency to augment LV hypertrophy, and increased non-cross-linked type I and type III myocardial collagen concentrations. Iso administration resulted in reduced pump function without modification of intrinsic myocardial systolic function. However, despite increasing myocardial non-cross-linked concentrations, Iso failed to alter myocardial k in SHRs. These results suggest that beta-AR-mediated rightward shifts in LV diastolic P-V relations, which induce decreased pump function, are mediated by chamber remodeling but not by modifications in myocardial material properties.     

Kidney Function,Endothelial Activation and Atherosclerosis in Black and White Africans with Rheumatoid Arthritis

Objective

To determine whether kidney function independently relates to endothelial activation and ultrasound determined carotid atherosclerosis in black and white Africans with rheumatoid arthritis (RA).

Methods

We calculated the Jelliffe, 5 Cockcroft-Gault equations, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (EGFR) equations in 233 (112 black) RA patients.

Results

The CKD-EPI eGFR was <90 ml/min/1.73m² in 49.1% and 30.6% of black and white patients, respectively (odds ratio (95% confidence interval) = 2.19 (1.28–3.75), p = 0.004). EGFRs were overall consistently associated with monocyte chemoattractant protein-1 and angiopoietin 2 concentrations in white patients, and with carotid intima-media thickness and plaque in black participants. Amongst black patients, plaque prevalence was 36.7% and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was not associated with plaque presence for the MDRD equation (p = 0.3), whereas the respective relationship was significant or borderline significant (p = 0.003 to 0.08) and of similar extent (p>0.1 for comparisons of AUC (SE)) for the other 8 equations. Based on optimal eGFR cutoff values with sensitivities and specificities ranging from 42 to 60% and 70 to 91% respectively, as determined in ROC curve analysis, a low eGFR increased the odds ratio for plaque 2.2 to 4.0 fold.

Conclusion

Reduced kidney function is independently associated with atherosclerosis and endothelial activation in black and white Africans with RA, respectively. CKD is highly prevalent in black Africans with RA. Apart from the MDRD, eGFR equations are useful in predicting carotid plaque presence, a coronary heart disease equivalent, amongst black African RA patients.     

Modeling of Cellular Arginine Uptake by More Than One Transporter

Determining the kinetic constants of arginine uptake by endothelial cells mediated by more than one transporter from linearization of data as Eadie-Hofstee plots or modeling which does not include the concentration of trace radiolabeled amino acid used to measure uptake may not be correct. The initial rate of uptake of trace [³H]l-arginine by HUVECs and ECV₃₀₄ cells in the presence of a range of unlabeled arginine and modifiers was used in nonlinear models to calculate the constants of arginine uptake using GraphPad Prism. Theoretical plots of uptake derived from constants determined from Eadie-Hofstee graphs overestimated uptake, whereas those from the nonlinear modeling approach agreed with experimental data. The contribution of uptake by individual transporters could be modeled and showed that leucine inhibited the individual transporters differently and not necessarily competitively. N-Ethylmaleimide inhibited only y⁺ transport, and BCH may be a selective inhibitor of y⁺L transport. The absence of sodium reduced arginine uptake by y⁺L transport and reduced the K _m′, whereas reducing sodium decreased arginine uptake by y⁺ transport without affecting the K _m′. The nonlinear modeling approach using raw data avoided the errors inherent in methods deriving constants from the linearization of the uptake processes following Michaelian kinetics. This study provides explanations for discrepancies in the literature and suggests that a nonlinear modeling approach better characterizes the kinetics of amino acid uptake into cells by more than one transporter.     

Susceptibility to systolic dysfunction in the myocardium from chronically infarcted spontaneously hypertensive rats

We explored whether the hypertensive heart is susceptible to myocardial dysfunction in viable noninfarcted tissue post-myocardial infarction (MI), the potential mechanisms thereof, and the impact of these changes on pump function. Six to seven months after the ligation of the left anterior descending coronary artery, left ventricular (LV) myocardial systolic function, as assessed from the percent shortening of the noninfarcted lateral wall segmental length determined over a range of filling pressures (ultrasonic transducers placed in the lateral wall in anaesthetized, open-chest, ventilated rats) and the percent thickening of the posterior wall (echocardiography), was reduced in infarcted spontaneous hypertensive rats (SHR-MI) (P < 0.05) but not in normotensive Wistar-Kyoto (WKY-MI) animals compared with corresponding controls [SHR-sham operations (Sham) and WKY-Sham]. This change in the regional myocardial function in SHR-MI, but not in WKY-MI, occurred despite a similar degree of LV dilatation (increased LV end-diastolic dimensions and volume intercept of the LV end-diastolic pressure-volume relation) in SHR-MI and WKY-MI rats and a lack of difference in LV relative wall thinning, LV wall stress, apoptosis [terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL)], or necrosis (pathological score) between SHR-MI and WKY-MI rats. Although the change in regional myocardial function in the SHR-MI group was not associated with a greater reduction in baseline global LV chamber systolic function [end-systolic elastance (LV E(es)) and endocardial fractional shortening determined in the absence of an adrenergic stimulus], in the presence of an isoproterenol challenge, noninfarct-zone LV systolic myocardial dysfunction manifested in a significant reduction in LV E(es) in SHR-MI compared with WKY-MI and SHR and WKY-Sham rats (P < 0.04). In conclusion, these data suggest that with chronic MI, the hypertensive heart is susceptible to the development of myocardial dysfunction, a change that cannot be attributed to excessive chamber dilatation, apoptosis, or necrosis, but which in turn contributes toward a reduced cardiac adrenergic inotropic reserve.     

Reduced cardiac stiffness following exercise is associated with preserved myocardial collagen characteristics in the rat

We determined whether the increment in cardiac end-diastolic compliance (a reduced diastolic stiffness constant) following endurance training is related to alterations in myocardial collagen characteristics. Sixteen weeks of habitual exercise (Ex) in rats, which produced left ventricular (LV) hypertrophy (LVH) [LV weight in g: Ex=1.01 (0.04), sedentary control = 0.89 (0.04); P<0.05], resulted in a reduced LV end-diastolic (LVED) chamber stiffness [slope of the linearised LVED pressure versus LVED internal diameter relation in kPa · mm⁻¹: Ex=0.67 (0.03), control=0.80 (0.03); P<0.05]. The increased LVED chamber distensibility was associated with an attenuated myocardial stiffness [slope of the linearised LVED stress versus strain relation in g · cm⁻²; Ex=15 (3), control=25 (2); P<0.05]. Although LV total collagen content (mg) was increased in the exercised rats [Ex=5.0 (0.3), control=4.1 (0.2); P<0.05], this was a reflection of the presence of LVH, as the myocardial collagen concentration (μg · mg⁻¹ LV wet weight) was unaltered [Ex=4.9 (0.2), control=4.6 (0.2)]. Furthermore, habitual exercise did not influence the percentage of myocardial collagen extracted following cyanogen bromide digestion (an index of collagen cross-linking), [i.e. Ex=38 (3), control=38 (3)], nor the proportion of myocardial collagen phenotypes I and III [I/III; Ex=3.04 (0.20), control=2.85 (0.22)]. In conclusion, exercise-induced increments in end-diastolic myocardial distensibility are unlikely to be a consequence of alterations in the properties of myocardial collagen. Accepted: 17 December 1997     

Mechanisms of preserved baseline cardiac systolic function in rats with adrenergic inotropic downregulation

Despite reductions in beta-adrenoreceptor (beta-AR)-mediated inotropic effects induced by sustained sympathetic activation in cardiac disease, whether these changes necessarily result in reductions in systolic function under resting conditions (baseline function) is not clear. Moreover, possible compensatory mechanisms which might contribute to maintaining the baseline systolic function despite reductions in beta-AR-mediated inotropic effects have not been systematically sought. In the present study, 1 month of daily administration of the beta-AR agonist, isoproterenol (0.05 mg/kg/day, i.p.), to rats resulted in an attenuation of left ventricular inotropic responses to isoproterenol over a wide range of concentrations (10(-8)-10(-4) M), whereas a decline of inotropic responses to norepinephrine, an endogenous inotrope, occurred only at high concentrations (10(-5)-10(-4) M). However, chronic isoproterenol administration failed to modify baseline systolic chamber and myocardial function, as determined in vivo using echocardiography (endocardial and midwall fractional shortening), and in isolated, perfused heart preparations (end-systolic chamber and myocardial elastance) Sustained baseline chamber function despite profound beta-AR-mediated inotropic downregulation was not attributed to alterations in cardiac loading conditions, resting heart rate, chamber remodeling, increased myocardial norepinephrine release, or enhanced contractile responses to alternative receptor/signal transduction pathways mediating positive inotropy (as assessed from histamine, serotonin, forskolin, angiotensin II or phenylephrine responsiveness). These findings indicate that baseline cardiac contractile function might be unaltered despite a profound impairment of beta-AR-induced responsiveness, an effect related to a preserved stimulatory influence of low physiological concentrations of endogenous norepinephrine constituting adrenergic tone at rest.     

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic beta-adrenoreceptor activation

There is no direct evidence to indicate that pump dysfunction in a dilated chamber reflects the impact of chamber dilatation rather than the degree of intrinsic systolic failure resulting from myocardial damage. In the present study, we explored the relative roles of intrinsic myocardial systolic dysfunction and chamber dilatation as mediators of left ventricular (LV) pump dysfunction. Administration of isoproterenol, a beta-adrenoreceptor agonist, for 3 mo to rats (0.1 mg.kg(-1).day(-1)) resulted in LV pump dysfunction as evidenced by a reduced LV endocardial fractional shortening (echocardiography) and a decrease in the slope of the LV systolic pressure-volume relation (isolated heart preparations). Although chronic beta-adrenoreceptor activation induced cardiomyocyte damage (deoxynucleotidyl transferase-mediated dUTP nick-end labeling) as well as beta(1)- and beta(2)-adrenoreceptor inotropic downregulation (attenuated contractile responses to dobutamine and salbutamol), these changes failed to translate into alterations in intrinsic myocardial contractility. Indeed, LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relation (isolated heart preparations) were unchanged. A normal intrinsic myocardial systolic function, despite the presence of cardiomyocyte damage and beta-adrenoreceptor inotropic downregulation, was ascribed to marked increases in myocardial norepinephrine release, to upregulation of alpha-adrenoreceptor-mediated contractile effects as determined by phenylephrine responsiveness, and to compensatory LV hypertrophy. LV pump failure was attributed to LV dilatation, as evidenced by increased LV internal dimensions (echocardiography), and a right shift and increased volume intercept of the LV diastolic pressure-volume relation. In conclusion, chronic sympathetic stimulation, despite reducing beta-adrenoreceptor-mediated inotropic responses and promoting myocyte apoptosis, may nevertheless induce pump dysfunction primarily through LV dilatation, rather than intrinsic myocardial systolic failure.     

Rheumatoid arthritis is associated with reduced adiposity but not with unfavorable major cardiovascular risk factor profiles and enhanced carotid atherosclerosis in black Africans from a developing population: a cross-sectional study

Introduction

Rheumatoid arthritis (RA) is characterized by inflamed joint-derived cytokine-mediated high-grade systemic inflammation that enhances cardiovascular metabolic risk and disease in developed populations. We investigated the potential impact of RA on cardiovascular risk factors including systemic inflammation and atherosclerosis, and their relationships in black Africans from a developing population.

Methods

We evaluated demographic features, adiposity indices, major traditional cardiovascular risk factors, circulating C-reactive protein and interleukin-6 concentrations and ultrasound determined carotid intima-media thickness (cIMT) in 274 black Africans; 115 had established RA. Data were analyzed in confounder-adjusted mixed regression models.

Results

The body mass index and waist-height ratio were lower in RA compared to non-RA subjects (29.2 (6.6) versus 33.7 (8.0), P < 0.0001 and 0.58 (0.09) versus 0.62 (0.1), P = 0.0003, respectively). Dyslipidemia was less prevalent in patients with RA (odds ratio (OR) (95% confidence interval (CI) = 0.54 (0.30 to1.00)); this disparity was no longer significant after further adjustment for reduced adiposity and chloroquine use. RA was also not associated with hypertension, current smoking and diabetes. The number of major traditional risk factors did not differ by RA status (1.1 (0.8) versus 1.2 (0.9), P = 0.7). Circulating C-reactive protein concentrations were similar and serum interleukin-6 concentrations reduced in RA (7.2 (3.1) versus 6.7 (3.1) mg/l, P = 0.7 and 3.9 (1.9) versus 6.3 (1.9) pg/ml, P < 0.0001, respectively). The cIMT was 0.700 (0.085) and 0.701 (0.111) mm in RA and non-RA subjects, respectively (P = 0.7). RA disease activity and severity parameters were consistently unrelated to systemic inflammation, despite the presence of clinically active disease in 82.6% of patients. In all participants, adiposity indices, smoking and converting angiotensin inhibitor non-use were associated with increased systemic inflammation, which related to more atherogenic lipid profiles, and circulating low density lipoprotein concentrations were associated with cIMT (partial R = 0.153, P = 0.032); RA did not impact on these relationships (interaction P ≥0.1).

Conclusions

Among black Africans, patients with established RA experience reduced overall and abdominal adiposity but no enhanced major traditional risk factor and atherosclerosis burden. This study further suggests that an absent interleukin-6 release by inflamed RA joints into the circulation may account for this unaltered cardiovascular disease risk.     

Independent associations of total and high molecular weight adiponectin with cardiometabolic risk and surrogate markers of enhanced early atherogenesis in black and white patients with rheumatoid arthritis: a cross-sectional study

IntroductionWhether adiponectin levels associate with atherogenesis in RA is uncertain. We examined the independent relationships of total and high molecular weight (HMW) adiponectin concentrations with cardiometabolic risk and surrogate markers of enhanced early atherogenesis in black and white patients with RA.MethodsWe determined total and HMW adiponectin concentrations and those of endothelial activation molecules including soluble E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), in 210 (119 black and 91 white) RA patients. Associations were determined in potential confounder and mediator adjusted mixed regression models.ResultsTotal and HMW adiponectin concentrations related similarly to metabolic risk factors and endothelial activation. In all patients, total and HMW adiponectin concentrations associated paradoxically with high systolic, diastolic and mean blood pressure (partial R = 0.155 to 0.241, P ≤0.03). Ethnic origin did not impact on these relationships (interaction P ≥0.09). Total and HMW adiponectin concentrations associated with those of glucose in white and black patients respectively (partial R = -0.304, P = 0.006 and -0.246, P = 0.01). In black but not white participants, total and HMW adiponectin concentrations also related favorably to lipid profiles (partial R = 0.292 to 0.360, P ≤0.003 for HDL cholesterol concentrations, -0.269 to -0.299, P ≤0.006 for triglyceride concentrations and -0.302 to -0.390, P ≤0.002 for total-HDL cholesterol ratio) and the number of metabolic risk factors (partial R = -0.210 to -0.238, P ≤0.03). In white but not black patients, total and HMW adiponectin concentrations associated paradoxically with overall endothelial activation as estimated by a standard z-score of endothelial activation molecule concentrations (partial R = 0.262, P = 0.01 and 0.252, P = 0.02); in the respective models, the extent of effect of total and HMW adiponectin concentrations on endothelial activation was larger in white compared to black participants (standardized β (SE) = 0.260 (0.107) versus -0.106 (0.107), P = 0.01 and 0.260 (0.120) versus -0.100 (0.111), P = 0.02). The HMW-total adiponectin ratio related inconsistently to metabolic risk factors and not to endothelial activation.ConclusionIn this study, total and HMW adiponectin concentrations associated with increased blood pressure parameters, and in white patients additionally with endothelial activation. The potential mechanism(s) underlying these paradoxical relationships between adiponectin concentrations and cardiovascular risk in RA merit further investigation.