Metformin Prevents Low-dose Isoproterenol-induced Cardiac Dilatation and Systolic Dysfunction in Male Sprague Dawley Rats.

ABSTRACT: Myocardial metabolic abnormalities are well-recognized alterations in chronic heart failure, effects that may contribute to progressive cardiac dysfunction. However, whether metabolic alterations in-part mediate their deleterious effects by modifying the chronic impact of excess low-dose sympathetic stimulation on cardiac chamber dilatation is uncertain. We therefore aimed to determine the effect of metformin administration on cardiac function and mitochondrial architectural changes in a rat model of chronic sympathetic-induced left ventricular (LV) remodeling and systolic dysfunction [daily subcutaneous isoproterenol (ISO) injection at a low dose of 0.02 mg/kg for 7 months]. Echocardiography was used to assess in vivo LV dimensions and function, and mitochondrial and myofibril arrangement was assessed using transmission electron microscopy. Seven months of low-dose ISO administration increased LV diastolic diameter (in mm) [control (CONT): 7.29 ± 0.19 vs. ISO: 8.76 ± 0.21; P = 0.001], an effect that was attenuated by metformin (ISO + MET: 7.63 ± 0.29 vs. ISO: P = 0.001) administration. Similarly, ISO increased LV end-systolic diameter (CONT: 4.43 ± 0.16 vs. ISO: 5.49 ± 0.16: P < 0.0001), an effect prevented by metformin (ISO + MET: 4.04 ± 0.25 vs. ISO: P < 0.0001). Moreover, chronic ISO administration reduced LV endocardial fractional shortening (P = 0.0001), midwall fractional shortening (P = 0.0001), and ejection fraction (P = 0.0001), effects similarly prevented by metformin administration. Furthermore, changes in mitochondrial arrangement and relative mitochondrial area (CONT: 37.7 ± 2.2 vs. ISO: 28.1 ± 2.9; P = 0.05) were produced by ISO administration, effects prevented by metformin. In conclusion, metformin offers cardiac protection against chronic sympathetic-induced LV dilatation and systolic dysfunction. These data support a role for myocardial metabolic changes in mediating LV dilatation and LV dysfunction produced by chronic neurohumoral activation in cardiac disease.

Marked Arterial Functional Changes in Patients With Arterial Vascular Events Across the Early Adult Lifespan.

OBJECTIVE: The age at which arteriosclerosis begins to contribute to events is uncertain. We determined, across the adult lifespan, the extent to which arteriosclerosis-related changes in arterial function occur in those with precipitous arterial events (stroke and critical limb ischemia). Approaches and Results: In 1082 black South Africans (356 with either critical limb ischemia [n=238] or stroke [n=118; 35.4% premature], and 726 age, sex, and ethnicity-matched randomly selected controls), arterial function was evaluated from applanation tonometry and velocity and diameter measurements in the outflow tract. Compared with age- and sex-matched controls, over 10-year increments in age from 20 to 60years, multivariate-adjusted (including steady-state pressures) aortic pulse wave velocity, characteristic impedance (Zc), forward wave pressures (Pf), and early systolic pulse pressure amplification were consistently altered in those with arterial events. Increases in Zc were accounted for by aortic stiffness (no differences in aortic diameter) and Pf by changes in Zc and not aortic flow or wave re-reflection. Multivariate-adjusted pulse wave velocity (7.48±0.30 versus 5.82±0.15 m/s, P<0.0001), Zc (P<0.0005), and Pf (P<0.0001) were higher and early systolic pulse pressure amplification lower (P<0.0001) in those with precipitous events than in controls. In comparison to age- and sex-matched controls, independent of risk factors, pulse wave velocity, and Zc (P<0.005 and <0.05) were more closely associated with premature events than events in older persons and Pf and early systolic pulse pressure amplification were at least as closely associated with premature events as events in older persons. CONCLUSIONS: Arteriosclerosis-related changes in arterial function are consistently associated with arterial events beyond risk factors from as early as 20 years of age.

Potential determinants of the E/e' ratio in non-dialysis compared with dialysis patients.

AIM: We hypothesized that arterial function and N-terminal natriuretic peptide (NT-proBNP) levels as a marker of volume overload, relate differently to E/e' as an index of diastolic function in dialysis compared with non-dialysis patients with chronic kidney disease. We further examined whether cardiovascular risk factors attenuated these relationships. METHODS: We assessed cardiovascular risk factors and determined arterial function indices by applanation tonometry using SphygmoCor software and E/e' by echocardiography in 103 (62 non-dialysis and 41 dialysis) patients. RESULTS: In established confounder adjusted analysis, dialysis status impacted the pulse wave velocity-E/e' relationship (interaction p = .01) but not the NT-proBNP level-E/e' association (interaction p = .1). Upon entering arterial function measures and NT-proBNP levels simultaneously in regression models, arterial function measures were associated with E/e' (p = .008 to .04) in non-dialysis patients whereas NT-proBNP levels were related to E/e' in dialysis patients (p = .009 to .04). Bivariate associations were found between diabetes (p < .0001) and E/e' in non-dialysis patients, and haemoglobin concentrations and E/e' (p = .02) in those on dialysis. Upon adjustment for diabetes in non-dialysis patients, only central pulse pressure remained associated with E/e' (p = .02); when haemoglobin concentrations were adjusted for in dialysis patients, NT-proBNP levels were no longer associated with E/e' (p = .2). In separate models, haemoglobin levels were associated with E/e' independent of left ventricular mass index and preload and afterload measures (p = .02 to .03). CONCLUSION: The main determinants of E/e' may differ in non-dialysis compared with dialysis patients. These include arterial function and diabetes in non-dialysis patients, and volume overload and anaemia in dialysis patients.

Associations between circulating resistin concentrations and left ventricular mass are not accounted for by effects on aortic stiffness or renal dysfunction.

BACKGROUND: Although, in-part through an impact on left ventricular mass (LVM), resistin (an adipokine) may contribute to heart failure, whether this is explained by the adverse effects of resistin on aortic stiffness and renal function is unknown. METHODS: Relationships between circulating resistin concentrations and LVM index (LVMI), and LVM beyond that predicted by stroke work (inappropriate LVM [LVMinappr]) (echocardiography) were determined in 647 randomly selected community participants, and in regression analysis, the extent to which these relations could be explained by aortic pulse wave velocity (PWV) or estimated glomerular filtration rate (eGFR) was evaluated. RESULTS: Independent of confounders, resistin concentrations were independently associated with LVMI, LVMinappr, LV hypertrophy (LVH), PWV and eGFR. Furthermore, independent of confounders, LVMI, LVMinappr and LVH were independently associated with PWV and eGFR. However, adjustments for either PWV or eGFR failed to modify the relationships between resistin concentrations and LVMI, LVMinappr or LVH. Moreover, in multivariate regression analysis neither PWV nor eGFR significantly modified the contribution of resistin to LVMinappr or LVMI. CONCLUSIONS: Independent relationships between circulating concentrations of the adipocytokine resistin and LVM are not explained by the impact of resistin on ventricular-vascular coupling or renal dysfunction. Resistin's effects on LVM are therefore likely to be through direct actions on the myocardium.

May Measurement Month 2018: an analysis of blood pressure screening results in South Africa.

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative of the International Society of Hypertension (ISH) aimed at raising awareness of high BP and acting as a temporary solution to the lack of screening programmes worldwide. As part of MMM, screening in South Africa in 2017 revealed that 24.5% of adults (mean age = 31 years) have hypertension and only half of those with hypertension had controlled BP. These data highlight the need for continued screening and awareness campaigns. An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2018. Blood pressure measurements, the definition of hypertension and statistical analyses followed the MMM protocol. The sites screened were general populations and university campuses in preference to hospitals and clinics, aiming to raise awareness and allow access to screening to those less likely to be aware of their BP. In total, 2965 individuals (age 40.5 ± 18.2 years) were screened. After multiple imputation for missing BP readings, 34.6% had hypertension, only 56.7% of those with hypertension were aware, 21.2% of those not receiving treatment for hypertension were hypertensive, and a large proportion (42.5%) of individuals receiving antihypertensive medication had uncontrolled BP. These results suggest that opportunistic screening campaigns can identify significant numbers with undiagnosed and uncontrolled hypertension. The high proportions of individuals with undiagnosed and treated uncontrolled hypertension highlight the need for hypertension awareness campaigns and more rigorous management of hypertension.

May Measurement Month 2017: an analysis of blood pressure screening results in South Africa-Sub-Saharan Africa.

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative of the International Society of Hypertension (ISH) aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programs worldwide. A surveillance study in 2016 in South Africa revealed that 45% of adults have hypertension and only 6-9% of men and women respectively had controlled BP on medication, highlighting the need for regular screening and awareness campaigns. An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2017. Blood pressure measurement, the definition of hypertension, and statistical analyses followed the MMM protocol. The sites screened were primarily university campuses and general populations in preference to hospitals and clinics, aiming to raise awareness and allow access to screening in those less likely to be aware of their BP. In total, 3250 individuals (mean age 31.0 ± 13.3 years) were screened. After multiple imputation for missing BP readings, 795 (24.5%) had hypertension. Of individuals not receiving antihypertensive medication, 459 (15.7%) were hypertensive, and 157 (46.9%) of individuals receiving antihypertensive medication had uncontrolled BP. These results suggest that opportunistic screening campaigns can identify significant numbers with undiagnosed and uncontrolled hypertension, even amongst the fairly young. The high proportions of individuals with undiagnosed and treated uncontrolled hypertension, highlight the need for campaigns to increase hypertension awareness and control.

Effects of High Salt-Low Potassium Diet on Blood Pressure and Vascular Reactivity in Male Sprague Dawley Rats.

Sodium (Na) intake increases vascular reactivity. Whether low potassium (K) intake affects vascular reactivity-associated blood pressure (BP) changes is uncertain. This study aimed to determine whether Na-induced increases in BP and vascular reactivity are altered by low K intake. Male Sprague Dawley rats were assigned to 3 dietary groups for 6 weeks: a standard Na-K diet (control, n = 12), a high Na-normal K diet (HS-NormK, n = 12), and a high Na-low K diet (HS-LowK, n = 12). BP was measured at baseline and after the dietary intervention. Na and K excretions and vascular reactivity were measured after the dietary intervention. The Na/K ratio was significantly higher in the HS-LowK compared with the other groups. Systolic and diastolic BPs increased significantly in the HS-NormK and HS-LowK groups. In mesenteric arteries, the dose-response curves for phenylephrine-induced contractions shifted to the left and the EC50 (mean ± SD) was significantly lower in the HS-NormK (0.51 ± 0.17 µM, P = 0.003) and HS-LowK (0.69 ± 0.14 µM, P = 0.005) groups compared with the control (3.24 ± 0.79 µM). Systolic (r = -0.58 P = 0.002) and diastolic (r = -0.61 P = 0.001) BPs were associated with the EC50 of phenylephrine-induced contraction in mesenteric arteries. High Na intake induces increased alpha-1 receptor responsiveness in mesenteric arteries, which may be responsible for the increase in BP and is not affected by low dietary K intake.

Limited Impact of ß-Adrenergic Receptor Activation on Left Ventricular Diastolic Function in Rat Models of Hypertensive Heart Disease.

BACKGROUND: Hypertension is a major cause of left ventricular (LV) diastolic dysfunction. Although ß-adrenergic receptor (ß-AR) blockers are often used to manage hypertension, the impact of ß-AR activation on LV lusitropic effects and hence filling pressures in the hypertensive heart with LV diastolic dysfunction is uncertain. METHODS: Using tissue Doppler imaging and Speckle tracking software, we assessed LV function in isoflurane anesthetised spontaneously hypertensive (SHR) and Dahl salt-sensitive (DSS) rats before and after ß-AR activation [isoproterenol (ISO) administration]. RESULTS: As compared to normotensive Wistar Kyoto control rats, or DSS rats not receiving NaCl in the drinking water, SHR and DSS rats receiving NaCl in the drinking water had a reduced myocardial relaxation as indexed by lateral wall e' (early diastolic tissue velocity at the level of the mitral annulus) and an increased LV filling pressure as indexed by E/e'. However, LV ejection fraction and deformation and motion were preserved in both SHR and DSS rats. The administration of ISO resulted in a marked increase in ejection fraction and decrease in LV filling volumes in all groups, and an increase in e' in SHR, but not DSS rats. However, after ISO administration, although E/e' decreased in DSS rats in association with a reduced filling volume, E/e' in SHR remained unchanged and SHR retained greater values than Wistar Kyoto control. CONCLUSIONS: The hypertensive heart is characterized by reductions in myocardial relaxation and increases in filling pressures, but ß-AR activation may fail to improve myocardial relaxation and when this occurs, it does not reduce LV filling pressures.

Arterial wave reflection and subclinical atherosclerosis in rheumatoid arthritis.

OBJECTIVES: Atherosclerotic cardiovascular disease risk is increased in rheumatoid arthritis (RA). Wave reflection occurs at arterial branching points, which are particularly prone to atherosclerosis. We explored the relationship of wave reflection with atherosclerosis in RA. METHODS: One hundred and sixty three RA patients (110 white, 31 Asian, 17 black and 5 of mixed ancestry) without cardiovascular disease participated. Arterial stiffness, wave reflection, pressure pulsatility, plaque in the extracranial carotid artery tree and the mean of the left and right common carotid arteries intima-thickness were determined. Associations were identified in multivariable regression models. RESULTS: One SD increase in reflected wave pressure (OR (95% CI) = 2.54 (1.41-4.44), p=0.001), reflection magnitude (OR (95% CI) = 1.84 (1.17-2.89), p=0.008), central pulse pressure (OR (95% CI) = 1.89 (1.12-3.22), p=0.02) and peripheral pulse pressure (OR (95% CI) = 2.09 (1.23-3.57), p=0.007) were associated with plaque. The association of wave reflection with plaque was independent of arterial stiffness and pressure pulsatility, and was present in both hypertensive and normotensive RA patients. In receiver operator characteristic curve analysis, the optimal cutoff value for reflected wave pressure in predicting plaque presence was 25 mmHg with a sensitivity, specificity, positive predictive value and negative predictive value of 45.2%, 89.3%, 78.6% and 66.2%, respectively; a reflected wave pressure of >25 mmHg was associated with plaque in univariate and adjusted analysis (p<0.0001 for both). Arterial function was not independently related to carotid intima-media thickness. CONCLUSIONS: Consideration and therapeutic targeting of wave reflection may improve cardiovascular disease prevention in RA.

Sex-Specific Effects of Adrenergic-Induced Left Ventricular Remodeling in Spontaneously Hypertensive Rats.

OBJECTIVE: The aim of this work was to determine whether adrenergic-induced left ventricular (LV) dilation and eccentric remodeling in pressure-overload hypertrophy is sex specific. METHODS AND RESULTS: Chronic ß-adrenoreceptor activation was produced in male and female spontaneously hypertensive rats (SHRs) by means of daily administration of isoproterenol (ISO; 0.04 mg/kg daily) from 9 to 15 months of age. LV chamber dimensions were determined in vivo by means of echocardiography and ex vivo in isolated perfused heart preparations. The acute hemodynamic response to ISO, the degree of myocardial necrosis and apoptosis, and collagen distribution were also assessed. Female SHRs demonstrated inotropic and chronotropic responses to ISO similarly to male SHRs. Compared with control subjects (saline solution vehicle), following chronic ISO administration, LV end-diastolic diameter (mm) was increased in male (ISO 7.8 ± 0.3 vs control 6.6 ± 0.2; P < .001) but not in female (ISO 6.3 ± 0.2 vs control 6.2 ± 0.2; P = .23) SHRs. Similarly, compared with control, ISO administration increased the volume intercept of the LV end-diastolic pressure-volume relation (mL) in male (ISO 0.31 ± 0.02 vs control 0.22 ± 0.01; P < .0001) but not in female (ISO 0.17 ± 0.01 vs control 0.17 ± 0.01; P = 1.00) SHRs. Relative wall thickness was also decreased in male SHRs receiving ISO but not in female SHRs receiving ISO. Chronic ISO administration increased the percentage of area covered by interstitial collagen in male but not in female SHRs. Finally, chronic adrenergic stimulation failed to influence LV chamber or myocardial systolic function in either male or female SHRs. CONCLUSIONS: Male SHRs are more susceptible to adrenergic-induced LV dilation and eccentric LV remodeling than female SHRs. These effects are associated with increased collagen deposition. In pressure-overload hypertrophy, LV dilation and eccentric LV remodeling occur before LV dysfunction in male rats.

Prevention of ßeta-adrenergic-induced Adverse Cardiac Remodeling by Gonadectomy in Male but Not Female Spontaneously Hypertensive Rats.

Chronic ß-adrenergic stimulation induces left ventricular (LV) remodeling in male but not in female spontaneously hypertensive rats (SHRs). However, the role of sex steroids in mediating these effects has not been determined. The aim of the present study was to assess the impact of gonadectomy on isoproterenol (ISO)-induced LV remodeling in SHR. Gonadectomy was performed on 9-month-old male and female SHR. LV remodeling was induced by daily ISO injection (0.04 mg/kg) for 6 months. LV dimensions and functions were determined in vivo by echocardiography and ex vivo using isolated perfused heart preparations. In males, ISO increased LV end diastolic (LVED) diameter in sham-operated (in millimeter, ISO: 8.12 ± 0.26 vs. Con: 6.67 ± 0.20, P = 0.0002) but not in castrated SHR (ISO: 6.97 ± 0.31 vs. Con: 6.53 ± 0.15, P = 0.66). Similarly, ISO increased the volume intercept of the LVED pressure-volume relationship in sham-operated (in milliliters, ISO: 0.26 ± 0.02 vs. Con: 0.19 ± 0.01, P = 0.01) but not in castrated SHR (ISO: 0.17 ± 0.02 vs. Con: 0.17 ± 0.01, P = 0.99). In females, ISO only increased LVED diameter (ISO: 6.43 ± 0.13 vs. Con: 6.07 ± 0.09, P = 0.027). However, ovariectomy did not modify any LV dimensions measured in vivo and ex vivo. In conclusion, testosterone may be responsible for the chronic ß-adrenergic-induced LV dilation and eccentric remodeling observed in male but not female SHR.

Omentin concentrations are independently associated with those of matrix metalloproteinase-3 in patients with mild but not severe rheumatoid arthritis.

Omentin is an adipokine that reportedly protects against cardiometabolic risk. We investigated the relationships between omentin concentrations and subclinical cardiovascular disease in rheumatoid arthritis (RA). Omentin concentrations were measured in 213 (104 black; 109 white) RA patients. Relationships of omentin levels with those of endothelial activation markers, ultrasound determined carotid intima-media thickness and plaque, and matrix metalloproteinase (MMP)-2, -3 and -9 that mediate altered plaque stability, were identified in confounder adjusted multivariate regression models. Omentin concentrations were inversely associated with MMP-3 levels [ß = -364 (0.113), p = 0.002]. This relationship was influenced by population origin, RA activity and the erythrocyte sedimentation rate and joint deformity count (interaction p value = 0.009, 0.04, 0.04 and 0.007, respectively). Accordingly, the omentin-MMP-3 concentration relationship was reproduced in white [ß (SE) = -0.450 (0.153), p = 0.0004)] but not black patients [ß (SE) = -0.099 (0.195), p = 0.6)], in participants with disease remission or mild disease activity [ß (SE) = -0.411 (0.139), p = 0.004] but not with moderate or severe RA activity [ß (SE) = -0.286 (0.202), p = 0.2], and in those with a small [ß (SE) = -0.534 (0.161), p = 0.001] but not large erythrocyte sedimentation rate [-0.212 (0.168), p = 0.2] and without [ß (SE) = -0.554 (0.165), p = 0.0001] but not with large joint deformity counts [-0.110 (0.173), p = 0.5]. Omentin levels were unrelated to endothelial activation and atherosclerosis. Among patients with RA, a lack of plaque stabilizing effects by omentin may contribute to the reported link between severe disease and increased cardiovascular risk. The association between concentrations of omentin and MMP-3 is population specific in RA.

Dependence of Cardiac Systolic Function on Elevated Fatty Acid Availability in Obese, Insulin-Resistant Rats.

BACKGROUND: Clinical data advocating an adverse effect of obesity on left ventricular (LV) systolic function independent of comorbidities is controversial. We hypothesized that in obesity with prediabetic insulin resistance, circulating fatty acids (FAs) become a valuable fuel source in the maintenance of normal systolic function. METHODS: Male Wistar rats were fed a high caloric diet for 32 weeks to induce obesity. Myocardial LV systolic function was assessed using echocardiography and isolated heart preparations. RESULTS: Aortic output was reduced in obese rat hearts over a range of filling pressures (for example: 15 cmH2O, obese: 32.6 ± 1.2 ml/min vs control: 46.2 ± 0.9 ml/min, P < .05) when perfused with glucose alone. Similarly, the slope of the LV end-systolic pressure-volume relationship decreased, and there was a right shift in the LV end-systolic stress-strain relationship as determined in Langendorff perfused, isovolumic rat heart preparations in the presence of isoproterenol (10(-8)M) (LV systolic stress-strain relationship and a reduced load-independent intrinsic systolic myocardial function, obese: 791 ± 62 g/cm(2) vs control: 1186 ± 74 g/cm(2), P < .01). The addition of insulin to the perfusion buffer improved aortic output, whereas the addition of FAs completely normalized aortic output. LV function was maintained in obese animals in vivo during an inotropic challenge. CONCLUSIONS: Elevated circulating FA levels may be important to maintain myocardial systolic function in the initial stages of obesity and insulin resistance.

Ethanol-Associated Cardiomyocyte Apoptosis and Left Ventricular Dilation Are Unrelated to Changes in Myocardial Telomere Length in Rats.

AIM: The aim of this work was to determine whether ethanol-associated myocardial apoptosis and cardiac dilation are related to myocardial telomere shortening in rats. METHODS AND RESULTS: Sprague-Dawley (SD) rats received either drinking water with (ethanol: n = 19) or without (control: n = 19) 5% (v/v) ethanol ad libitum, for 4 months. Left ventricular (LV) dimensions and function (echocardiography and isolated perfused heart preparations), cardiomyocyte apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling), and leukocyte and myocardial telomere length (real-time polymerase chain reaction) were determined at the end of the study. Ethanol administration resulted in a marked increase in cardiomyocyte apoptosis (ethanol 0.85 ± 0.13% vs control 0.36 ± 0.06%; P = .0021) and LV dilation (LV end-diastolic diameter: ethanol 8.20 ± 0.14 mm vs control 7.56 ± 0.11 mm [P = .0014]; volume intercept at 0 mm Hg (V0) of the LV end-diastolic pressure-volume relationship: ethanol 0.40 ± 0.03 mL vs control 0.31 ± 0.02 mL [P = .020]). However, there were no changes in systolic chamber function as indexed by LV endocardial fractional shortening or the slope of the LV systolic pressure-volume relationship (end systolic elastance). The percentage of myocardial apoptosis was correlated with the degree of LV dilation (% apoptosis vs LV EDD: r = 0.39; n = 38; P = .021; vs V0: r = 0.44; n = 19; P = .046). No differences in leukocyte or cardiac telomere length were noted between the ethanol and control groups. Furthermore, cardiac telomere length was not associated with indexes of LV dilation (LVEDD and V0) or cardiomyocyte apoptosis. CONCLUSIONS: Chronic ethanol-associated myocardial apoptosis and adverse remodeling occurs independently from changes in cardiac telomere length. Telomere shortening may not be a critical mechanism responsible for cardiomyocyte apoptosis and adverse cardiac remodeling.

Telomere length, endothelial activation and carotid atherosclerosis in black and white African patients with rheumatoid arthritis.

OBJECTIVES: Our objective was to examine associations of traditional and non-traditional cardiovascular risk factors with relative leukocyte telomere length and confounder adjusted relationships of relative telomere length with endothelial activation and carotid atherosclerosis in black and white African patients with rheumatoid arthritis (RA). METHODS: Relative telomere length of leukocyte DNA in whole blood was determined using quantitative RT-PCR in 205 (101 black) African patients with RA. RESULTS: In demographic characteristic adjusted analysis, relative telomere length tended to be larger in black compared to white patients (median (IQR)=0.54 (0.42-0.54) and 0.48 (0.37-0.60) (p=0.07), respectively). In black patients, waist circumference, systolic, diastolic and mean blood pressure were associated with relative telomere length (ß (SE)=-0.00270 (0.00114) (p=0.02), -0.00185 (0.00060) (p=0.003), -0.00243 (0.00112) (p=0.03) and -0.00225 (0.00075) (p=0.003), respectively); in white patients, age, anti-cyclic citrullinated antibody positivity, biologic agent use, a cholesterol-HDL cholesterol ratio of >4 and the number of major traditional risk factors were related to relative telomere length (ß (SE) =-0.00242 (0.00113) (p=0.03), 0.06629 (0.03374) (p=0.05), -0.09321 (0.04310) (p=0.03), 0.08225 (0.03420) (p=0.02) and 0.04046 (0.01719) (p=0.02), respectively). One SD increase in relative telomere length was associated with carotid plaque (OR (95% CI)=1.65 (0.99-2.75) (p=0.05)) and vascular cell adhesion molecule-1 concentrations (ß (SE)=-0.05031 (0.02480) (p=0.04)) in black and white patients, respectively. CONCLUSIONS: This study disclosed paradoxically direct relationships between relative telomere length and cardiovascular risk factors in white and atherosclerosis in black African RA patients. The role of relative telomere length in cardiovascular risk and its stratification in RA requires longitudinal investigation.

Post-exercise effects on aortic wave reflection derived from wave separation analysis in young- to middle-aged pre-hypertensives and hypertensives.

PURPOSE: Decreases in brachial blood pressure (BP) may occur for several hours following a bout of exercise. Although aortic backward waves predict cardiovascular damage independent of brachial BP, whether decreases in aortic backward waves also occur post-exercise in young-to-middle-aged hypertensives, the extent to which these changes exceed brachial BP changes, and the best method of identifying these changes is uncertain. METHODS: We examined aortic function at baseline and 15-min post-exercise in 20 pre-hypertensive or hypertensive men and women (age 45 ± 7 years). Central aortic pressure, forward (Pf) and backward (Pb) wave pressures, the reflection index (RI) and augmentation pressure (AP) and index (AIx) were determined using applanation tonometry, and SphygmoCor software. RESULTS: Decreases in central aortic (p < 0.001) but not brachial systolic BP and pulse pressure (PP) occurred post-exercise. In addition, decreases in post-exercise (baseline versus post-exercise) Pb (19 ± 4 vs 13 ± 3 mm Hg p < 0.0001), RI (72.9 ± 22.1 vs 47.6 ± 12.8 %, p < 0.0001), AIx (26.3 ± 10.8 vs 7.8 ± 11.6 %, p < 0.0001) and AP (9.9 ± 3.9 vs 2.8 ± 3.9 mm Hg, p < 0.0001), but not Pf, were noted. However, decreases in AIx were not correlated with decreases in Pb, and whilst decreases in aortic PP correlated with decreases in Pb (p < 0.0001), no correlations were noted with decreases in AP or AIx. CONCLUSION: In young-to-middle-aged pre-hypertensive and hypertensive individuals, aortic backward waves decrease post-exercise; this change is not reflected in brachial BP measurements and is poorly indexed by measures of pressure augmentation.

Obesity and left ventricular hypertrophy: the hypertension connection.

The detection of left ventricular hypertrophy (LVH) is recommended for risk prediction, and changes in LV geometry may provide further prognostic information. Obesity is a major determinant of LVH, but the approach to LVH detection in obese hypertensives remains a challenge. In the present review, we discuss evidence leading to the recent acceptance of the use of LV mass indexed to height(2.7) or height(1.7) rather than body surface area, for LVH detection and its regression in obesity. We also review recent findings which indicate that obesity-induced LVH may be associated with concentric LV remodeling, and hence, that the presence of concentric LVH in obesity should not be assumed to indicate a cause of LVH other than obesity. We also discuss recent evidence for obesity and blood pressure producing additive and interactive effects on LV mass, and hence, that weight loss and blood pressure reduction are required to achieve appropriate regression.

Impact of castration on changes in left ventricular diastolic pressure-volume relations induced by chronic adrenergic stimulation in rats.

A reduced testosterone concentration characterizes heart failure and independently predicts outcomes. Although testosterone replacement therapy may have non cardiac-related therapeutic benefits in heart failure, whether reduced testosterone concentrations protect against adverse left ventricular remodeling (LV dilatation) is uncertain. We therefore evaluated whether surgical castration modifies LV dilatation after 6 months of daily injections of the ß-adrenergic receptor (AR) agonist, isoproterenol (ISO) (0.015 mg·kg(-1)·d(-1)), to rats. The extent of LV dilatation and LV systolic chamber dysfunction were determined using both echocardiography and isolated perfused heart procedures. The extent of LV dilatation was determined from LV diastolic pressure-volume (P-V) relationships. As compared with the saline vehicle-treated group, after 6 months of ß-AR activation in sham-castrated rats, a marked right shift in the LV diastolic P-V relationship was noted with an increased LV volume intercept at 0 mm Hg diastolic pressure (LV V(0) in milliliters) (ISO = 0.38 ± 0.02, saline vehicle = 0.30 ± 0.02, P < 0.05). However, chronic ß-AR activation did not alter LV systolic chamber function either in vivo (LV endocardial fractional shortening, echocardiography) or ex vivo (LV end systolic elastance). Although castration decreased body weight, castration failed to modify the impact of ISO on the LV diastolic P-V relationships or the LV volume intercept at 0 mm Hg diastolic pressure (LV V(0) in milliliters) (castration ISO = 0.35 ± 0.02, castration saline vehicle = 0.27 ± 0.03, P < 0.05). In conclusion, castration does not influence the extent of LV dilatation induced by chronic adrenergic activation in an animal model, where adverse LV remodeling precedes LV systolic chamber dysfunction.

Age impacts on the independent relationships of leptin with cardiometabolic risk and surrogate markers of enhanced early atherogenesis in black and white patients with rheumatoid arthritis: a cross-sectional study.

We examined the potential impact of demographic characteristics on the independent leptin-metabolic cardiovascular risk factor and leptin-endothelial activation relationships in black and white patients with RA. Leptin concentrations and those of endothelial activation molecules including soluble E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were measured in 217 RA patients (51.6% black). We determined associations in potential confounder and mediator-adjusted mixed regression models. No independent associations between leptin concentrations and cardiovascular risk were present in all patients and either women and men or black and white patients. However, age impacted on several leptin-cardiovascular risk relations (interaction P < 0.05). In patients aged <50 years (lower quartile), after but not before adjustment for waist circumference and body mass index in addition to other confounders, leptin concentrations associated with overall endothelial activation as estimated by an SD (z) score of endothelial activation molecule concentrations (partial R = 0.341, P = 0.04). In patients aged 50-58 years (second quartile), leptin concentrations related to those of HDL cholesterol (partial R = -0.365, P = 0.01) and total cholesterol-HDL cholesterol ratio (partial R = 0.299, P = 0.04), and in those aged 59-63 years (third quartile), paradoxically related to low systolic and mean blood pressure (partial R = -0.438, P = 0.005 and partial R = -0.370, P = 0.02, respectively). Patients with RA aged <50 years experience an independent adiposity-driven leptin-endothelial activation relationship in the absence of leptin-metabolic risk factor associations. Young but not older patients with RA may sustain obesity-induced endothelial activation that is directly mediated by leptin.

Adiponectin and atherosclerosis in rheumatoid arthritis.

In the present study, we examined the potential impact of adiponectin on carotid ultrasound determined atherosclerosis in 210 (119 black and 91 white) RA patients in mixed regression models. Total adiponectin concentrations were smaller in patients with compared to those without the metabolic syndrome (MetS) defined waist criterion (median (range) = 6.47 (1.23-34.54) versus 8.38 (0.82-85.30) ng/mL, P = 0.02, resp.); both total and high molecular weight (HMW) adiponectin concentrations were larger in patients with compared to those without joint deformities (7.97 (0.82-85.30) and 3.51 (0.01-35.40) versus 5.36 (1.29-19.49) and 2.34 (0.01-19.49) ng/mL, P = 0.003 and 0.02, resp.). Total and HMW adiponectin concentrations were associated with carotid artery plaque in patients with MetS waist (odds ratio (95% CI) = 0.87 (0.76-0.99) and 0.92 (0.85-0.99) per 1-standard deviation increment, P = 0.02 for both) and those without joint deformities (odds ratio (95% CI) = 0.94 (0.88-0.99) and 0.94 (0.89-0.99), P = 0.03 for both). Plaque prevalence was lower in patients without compared to those with joint deformities (23.4% versus 42.6, P = 0.004 in multivariable analysis). In RA patients with abdominal obesity or no clinically evident joint damage, adiponectin concentrations are reduced but nevertheless associated with decreased carotid atherosclerosis.