Neonatal administration of fenofibrate had no developmental programming effect on the lipid profile and relative leucocyte telomere lengths of adolescent rats fed a high-fructose diet postnatally.

Telomere length, a marker of ageing, is susceptible to developmental programming that may cause its accelerated attrition. Metabolic syndrome triggers telomere attrition. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, is protective against telomere attrition. We investigated the impact of fenofibrate administered during suckling on the lipid profile and leucocyte telomere lengths of rats fed a high-fructose diet post-weaning. Suckling Sprague-Dawley pups (n = 119) were allocated to four groups and gavaged with either 10 mL·kg-1 body mass 0.5% dimethyl sulfoxide, 100 mg·kg-1 body mass fenofibrate, fructose (20%, w / v), or a combination of fenofibrate and fructose for 15 days. Upon weaning, each of the initial groups was split into two subgroups: one had plain water while the other had fructose solution (20%, w / v) to drink for 6 weeks. Blood was collected for DNA extraction and relative leucocyte telomere length determination by real-time PCR. Plasma triglycerides and cholesterol were also quantified. The treatments had no effect (p > 0.05) on body mass, cholesterol concentration, and relative leucocyte telomere lengths in both sexes. Post-weaning fructose increased triglyceride concentrations (p < 0.05) in female rats. Fenofibrate administered during suckling did not affect ageing nor did it prevent high fructose-induced hypertriglyceridaemia in female rats.

ß-Sitosterol mitigates the development of high-fructose diet-induced nonalcoholic fatty liver disease in growing male Sprague-Dawley rats.

Fructose contributes to the development of nonalcoholic fatty liver disease (NAFLD). ß-Sitosterol (Bst), a naturally occurring phytosterol, has antihyperlipidaemic and hepatoprotective properties. This study interrogated the potential protective effect of ß-sitosterol against NAFLD in growing rats fed a high-fructose diet, modelling children fed obesogenic diets. Forty-four 21 day old male rat pups were randomly allocated to and administered the following treatments for 12 weeks: group I, standard rat chow (SRC) + plain drinking water (PW) + plain gelatine cube (PC); group II, SRC + 20% w/v fructose solution (FS) as drinking fluid + PC; group III, SRC + FS + 100 mg/kg fenofibrate in a gelatine cube; group IV, SRC + FS + 20 mg/kg ß-sitosterol gelatine cube (Bst); group V, SRC + PW + Bst. Terminally, the livers were dissected out, weighed, total liver lipid content determined, and histological analyses done. Harvested plasma was used to determine the surrogate biomarkers of liver function. The high-fructose diet caused increased (p < 0.05) hepatic lipid (total) accretion (>10% liver mass), micro- and macrovesicular hepatic steatosis, and hepatic inflammation. ß-Sitosterol and fenofibrate prevented the high-fructose diet-induced macrovesicular steatosis and prevented the progression of NAFLD to steatohepatitis. ß-Sitosterol can prospectively be used to mitigate diet-induced NAFLD.

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.

Telomere length and adrenergic-induced left ventricular dilatation and systolic chamber dysfunction in rats.

PURPOSE: The mechanisms responsible for telomere shortening in heart failure are uncertain. We evaluated whether left ventricular (LV) dilatation and systolic chamber dysfunction produced by chronic ß-adrenergic receptor (ß-AR) activation is associated with leukocyte or cardiac telomere shortening. METHODS: Following 6 months of daily injections of the ß-AR agonist, isoproterenol (0.02 mg/kg/day) or the saline vehicle to rats, the extent of LV dilatation and LV systolic chamber dysfunction were determined using echocardiography and isolated perfused heart procedures, and relative telomere length of leukocyte (LTL) and cardiac (CTL) deoxyribonucleic acid were determined using a quantitative real-time polymerase chain reaction assay. RESULTS: ß-AR activation resulted in LV dilatation as indexed by increased LV diastolic diameters (9.2 ± 0.6 vs. 8.4 ± 0.9 mm, P = 0.01) and increased diastolic volume intercepts at zero pressure of the LV diastolic pressure-volume relationship (isolated, perfused heart preparation) (0.40 ± 0.06 vs. 0.37 ± 0.08 ml, P = 0.03). Moreover, ß-AR activation resulted in LV systolic chamber dysfunction as indexed by reductions in LV endocardial fractional shortening (0.40 ± 0.05 vs. 0.45 ± 0.06, P = 0.01) and the slope of the LV systolic pressure-volume relation (609 ± 176 vs. 901 ± 230, P = 0.01). Although LTL decreased with age in rats receiving either the ß-AR agonist or the saline vehicle (P < 0.05), neither CTL (-0.10 ± 0.14 vs. -0.15 ± 0.12, P = 0.3) nor LTL (-0.11 ± 0.19 vs. -0.15 ± 0.18, P = 0.5) were modified by ß-AR activation. CONCLUSION: In conclusion, chronic ß-AR activation sufficient to produce LV dilatation and systolic chamber dysfunction is not associated with alterations in leukocyte or cardiac telomere length. Telomere shortening in chronic heart failure is unlikely to be attributed to chronic ß-AR activation.

Gene variants of the renin-angiotensin system and hypertension: from a trough of disillusionment to a welcome phase of enlightenment?

There is substantial evidence to suggest that BP (blood pressure) is an inherited trait. The introduction of gene technologies in the late 1980s generated a sharp phase of over-inflated prospects for polygenic traits such as hypertension. Not unexpectedly, the identification of the responsible loci in human populations has nevertheless proved to be a considerable challenge. Common variants of the RAS (renin-angiotensin system) genes, including of ACE (angiotensin-converting enzyme) and AGT (angiotensinogen) were some of the first shown to be associated with BP. Presently, ACE and AGT are the only gene variants with functional relevance, where linkage studies showing relationships with hypertension have been reproduced in some studies and where large population-based and prospective studies have demonstrated these genes to be predictors of hypertension or BP. Nevertheless, a lack of reproducibility in other linkage and association studies has generated scepticism that only a concerted effort to attempt to explain will rectify. Without these explanations, it is unlikely that this knowledge will translate into the clinical arena. In the present review, we show that many of the previous concerns in the field have been addressed, but we also argue that a considerable amount of careful thought is still required to achieve enlightenment with respect to the role of RAS genes in hypertension. We discuss whether the previously identified problems of poor study design have been completely addressed with regards to the impact of ACE and AGT genes on BP. In the context of RAS genes, we also question whether the significance of 'incomplete penetrance' through associated environmental, phenotypic or physiological effects has been duly accounted for; whether appropriate consideration has been given to epistatic interactions between genes; and whether future RAS gene studies should consider variation across the gene by evaluating 'haplotypes'.

Impact of aldosterone receptor blockade on the deleterious cardiac effects of adrenergic activation in hypertensive rats.

Although in hypertension beta-adrenoreceptor activation promotes the transition from cardiac hypertrophy to pump dysfunction, the use of beta-blockers is controversial. As adrenergic activation may mediate adverse effects on the heart through the renin-angiotensin-aldosterone system, we evaluated the effects of the aldosterone receptor blocker, spironolactone (SPIRO), on isoproterenol (ISO)-induced changes in left ventricular cavity size and pump function and the determinants thereof in spontaneously hypertensive rats (SHR). ISO administered for 4.5 months resulted in increases in left ventricular dimensions and a decrease in pump function in SHR but not in normotensive rats, changes that, without affecting blood pressure, were abolished by SPIRO. In SHR, 4-5 days of ISO increased myocardial matrix metalloproteinase-2 activity, which was associated with matrix metalloproteinase-2 but not tissue inhibitor of MMP expression; persisted at 4.5 months; and was prevented by SPIRO. Moreover, after 4.5 months, ISO increased non-cross-linked myocardial collagen concentrations in SHR, which was abolished by SPIRO. Although after 4.5 months, ISO was not associated with increased cardiomyocyte apoptosis, an early (4-5 days) ISO-induced apoptotic effect was noted, which was prevented by SPIRO. Hence, aldosterone receptor blockade may be sufficient to prevent those adverse effects of beta-adrenoreceptor activation responsible for the transition from concentric cardiac hypertrophy to pump dysfunction in hypertension.

ß-Sitosterol Shows Potential to Protect Against the Development of High-Fructose Diet-Induced Metabolic Dysfunction in Female Rats.

Metabolic syndrome (MetS) is a combination of risk factors that include insulin resistance, obesity, dyslipidemia, and hypertension. The consumption of high-fructose diets contributes to the development of MetS. ß-sitosterol a naturally occurring phytosterol possesses antiobesogenic and antidiabetic effects. This study evaluated the potential protective effect of ß-sitosterol against the development of metabolic dysfunction in growing female rats fed a high-fructose diet, mimicking children fed obesogenic diets. Thirty-five 21-day-old female Sprague Dawley rat pups were randomly allocated to and administered the following treatments: group 1-standard rat chow (SRC) + plain drinking water (PW) + plain gelatine cube (PC); group 2-SRC + 20% w/w fructose solution (FS) as drinking fluid + PC; group 3-SRC + FS + 100 mg/kg fenofibrate in gelatine cubes; group 4-SRC + FS + 20 mg/kg ß-sitosterol gelatine cube (Bst); and group 5-SRC + PW + Bst. Following 12 weeks of feeding, the rats were fasted overnight, weighed, and then euthanized. Plasma cholesterol, insulin, glucose, triglyceride, and adiponectin concentrations were determined. Visceral fat was dissected out and weighed. The high-fructose diet increased (P < .05) visceral adiposity and plasma triglyceride concentration but decreased (P < .05) plasma adiponectin concentration. ß-sitosterol prevented the high-fructose diet-induced visceral obesity, hypertriglyceridemia, and hypoadiponectinemia. ß-sitosterol alone increased plasma adiponectin concentration and reduced plasma insulin concentration and homeostatic model assessment index. In conclusion, ß-sitosterol could be potentially used to prevent high-fructose diet-induced metabolic dysfunction.

Nurse-recorded auscultatory blood pressure at a single visit predicts target organ changes as well as ambulatory blood pressure.

AIM: To determine whether high-quality nurse-recorded auscultatory blood pressure (BP) values obtained at a single visit predict cardiovascular target organ changes as closely as ambulatory BP measurements. METHODS: In a randomly selected population sample (n = 458, 21% receiving antihypertensive treatment; approximately 40% hypertensive), we compared high-quality single visit nurse-recorded auscultatory BP values to same-day 24-h ambulatory BP in their ability to predict multiple target organ changes [left ventricular mass index (LVMI), left ventricle (LV) mean wall thickness (MWT), early-to-late transmitral velocity ratios (E/A), (echocardiography); log of urinary albumin-to-creatinine ratios (log ACR) (24-h urine samples); large artery dysfunction [carotid-femoral pulse wave velocity (PWV) and central augmentation index (Alc) (applanation tonometry)]. RESULTS: Nurse-recorded systolic BP (SBP) measurements obtained at a single visit were as closely associated with LVMI (r = 0.44), LV MWT (r = 0.44), E/A (r = -0.55), log ACR (r = 0.20), PWV (r = 0.62) and AIc (r = 0.41) (P < 0.0001 for all relations) as was 24-h SBP (LVMI; r = 0.33, LV MWT; r = 0.37, E/A; r = -0.35, log ACR; r = 0.24, PWV; r = 0.41, and AIc; r = 0.18, P < 0.001 for all relations) and either day or night SBP. On multivariate regression analysis with both nurse-recorded SBP and 24-h SBP in the same model, nurse-recorded SBP was independently associated with LVMI (P = 0.006), LV MWT (P = 0.03), E/A (P < 0.02), PWV (P < 0.0001) and AIc (P = 0.0002), and 24-h SBP was independently and positively associated with log ACR (P < 0.005), and PWV (P = 0.01). CONCLUSION: One or more, high-quality single visit nurse-recorded auscultatory BP measurements may be equally as effective as ambulatory BP in predicting target organ damage in a population sample of African ancestry.

The association of waist circumference with ambulatory blood pressure is independent of alternative adiposity indices.

AIM: The relationship between waist circumference (WC) and conventional blood pressure (BP) is independent of other clinical indices of adiposity. As ambulatory BP may offer more prognostic information than conventional BP, we aimed to identify whether indices of central adiposity are associated with ambulatory BP independent of other indices of adiposity. METHODS: The relationship between indices of adiposity [WC, waist-to-hip ratio, body mass index (BMI) or skin-fold thickness] and ambulatory or conventional BP was determined in 300 randomly selected individuals of African descent living in an urban developing community in South Africa. Relationships were determined with multiple indices of adiposity in the same regression model and after adjusting for age, gender, alcohol and tobacco intake, the presence or absence of diabetes mellitus or inappropriate blood glucose control [haemoglobin A1c (HbA1c)], antihypertensive therapy and menopausal status. RESULTS: Sixty-five per cent of participants were overweight or obese. With respect to the relationships between indices of adiposity, BMI and WC showed the strongest correlation (r=0.84, P<0.0001). After including all indices of adiposity and confounders in the model, WC was the only clinical index of adiposity which independently predicted 24-h (partial r=0.15, P<0.005) and conventional (partial r=0.14, P<0.005) systolic BP and 24-h (partial r=0.13, P<0.02) and conventional (partial r=0.40, P<0.0001) diastolic BP. After adjusting for other adiposity indices and confounders, every 1 SD (15 cm) increase in WC resulted in a 4.04 mmHg increase in 24-h systolic BP and a 4.33 mmHg increase in 24-h diastolic BP. Similar results were obtained in the subgroup of 237 participants not receiving antihypertensive therapy. CONCLUSION: WC is the only clinical index of adiposity that is associated with 24-h and conventional BP independent of other adiposity indices in a community with a high prevalence of obesity.

Functional variants of the angiotensinogen gene determine antihypertensive responses to angiotensin-converting enzyme inhibitors in subjects of African origin.

OBJECTIVE: To determine whether the response to angiotensin-converting enzyme inhibitor (ACEI) monotherapy in subjects of African origin is determined by genetic variants within the angiotensinogen (AGT) gene. METHODS: A total of 194 hypertensive patients of African ancestry were recruited from district clinics in Johannesburg, South Africa. Eighty patients received open-label ACEI (enalapril or lisinopril) monotherapy, and 114 open-label calcium antagonist (nifedipine) as a drug class comparator. Twenty-four hour ambulatory blood pressure (ABP) monitoring was performed at baseline (off medication) and after 2 months of therapy. DNA was analysed for functional variants (-217G-->A and -20A-->C) of the AGT gene. The impact of genotype on ABP responses to ACEI monotherapy or calcium antagonists; and on plasma aldosterone and renin levels after ACEI monotherapy was assessed. RESULTS: Adjusting for baseline ABP and type of ACEI in the ACEI-treated group, the -217G-->A variant predicted ABP responses to ACEI (n = 77; P < 0.01), but not to nifedipine (n = 108). ACEI in patients with the AA genotype of the -217G-->A variant failed to elicit an antihypertensive response [change in ABP, mmHg: systolic blood pressure (SBP) +0.84 +/- 2.89, P = 0.78; diastolic blood pressure (DBP) -0.47 +/- 1.74, P = 0.79]. In contrast, those patients with at least one copy of the -217G allele developed a 7.23 +/- 1.55 and 5.38 +/- 1.12 mmHg decrease (P < 0.0001) in SBP and DBP, respectively, after ACEI administration. Similarly, the -20A-->C variant predicted ABP responses to ACEI monotherapy (P < 0.01) but not to nifedipine. Moreover, patients who were AA genotype for both variants failed to develop an antihypertensive response to ACEI (change in ABP, mmHg: SBP +1.06 +/- 3.05, P = 0.73; DBP -0.39 +/- 1.83, P = 0.83); whereas patients with at least one copy of both the -217G and the -20C allele developed substantial decreases in ABP (change in ABP, mmHg: SBP -14.08 +/- 3.72, P < 0.0001; DBP -9.62 +/- 2.74, P < 0.0001). Patients with at least one copy of the -217G allele demonstrated a significant reduction in the aldosterone-to-renin ratio (-0.098 +/- 0.035, P < 0.01), whereas in those patients who were -217AA genotype the ratio was unchanged (-0.03 +/- 0.16, P = 0.85). CONCLUSION: Functional variants of the AGT gene contribute to the variability of antihypertensive responses to ACEI monotherapy in individuals of African ancestry, with genotype determining whether or not responses occur.

Angiotensinogen gene promoter region variant modifies body size-ambulatory blood pressure relations in hypertension.

BACKGROUND: The extent to which genes modify the relationship between risk factors for hypertension and blood pressure (BP) is unclear. As angiotensinogen is expressed in adipose tissue and angiotensinogen (AGT) gene promoter variants influence the production of angiotensinogen, we evaluated the role of AGT gene variants as potential modifiers of body size-BP relations. METHODS AND RESULTS: Five hundred twenty-one hypertensives of African origin sampled from a group with a high mean body mass index (BMI) had 24-hour ambulatory BP (ABP) measurements determined off therapy and were genotyped for the AGT -6G-->A, -532C-->T, -20A-->C, and 704T-->C (M235T) gene variants. Genotypes were also determined in 547 control subjects of African origin who had a normal clinic BP. The -6A and -532C alleles were concordant with the M235T variant. Although AGT gene variants had no independent effects on either the presence of hypertension or ABP values in hypertensives, the -20A-->C polymorphism had a marked influence on the relation between ambulatory systolic BP and BMI. This relation was present in patients homozygous for the -20A allele (n=399, r=0.23, P<0.0001), but absent in those with at least one copy of the -20C allele (n=122, r=0.01, P=0.89). The M235T polymorphism did not impact on the BMI-BP relation. Specificity of the -20A-->C polymorphism effect on the BMI-BP relation is further indicated by the lack of effect on the systolic BP-age relation. CONCLUSION: An AGT gene promoter region variant is an important modifier of the relation between body size and BP. Hence, these data corroborate the notion that genetic modifiers can produce a profound impact on BP-phenotypic relations.

An aldosterone synthase gene variant is associated with improvement in left ventricular ejection fraction in dilated cardiomyopathy.

OBJECTIVE: To assess whether renin-angiotensin-aldosterone (RAA) system gene polymorphisms shown to be associated with alterations in the activity of the system, may predict cardiac function changes subsequent to initiating medical therapy in heart failure. METHODS: The impact of RAA system genotypes on left ventricular ejection fraction (LVEF) following therapy to patients with idiopathic dilated cardiomyopathy (IDC) and class II-III heart failure was assessed. In 107 patients LVEF and LV dimensions were determined using radionuclide ventriculography and echocardiography prior to and subsequent to receiving furosemide, digoxin and angiotensin-converting enzyme (ACE) inhibitor therapy. Patients and controls were genotyped for variants of the ACE (insertion-deletion polymorphism), angiotensinogen (AGT; M235T polymorphism) and the aldosterone synthase (CYP11B2, C-344T polymorphism) genes. RESULTS: RAA system genotypes were not significantly associated with LVEF prior to initiating medical therapy. However, the CYP11B2 gene variant (P=0.0064 on covariate analysis [adjusted for multiple genotyping] with a 1-2% chance of false positive data), but neither the ACE, nor the AGT variants, predicted improvement in LV ejection fraction in patients on medical therapy. CONCLUSION: A CYP11B2 gene variant predicts the variable improvement in LV ejection fraction that occurs subsequent to initiating medical therapy in IDC. These data suggest a role for the aldosterone synthase locus in regulating the progression of heart failure.

Cross-linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodelling in hypertension in rats.

OBJECTIVE: To assess whether the variable impact of quantitative changes in myocardial collagen on left ventricular (LV) diastolic myocardial stiffness (myocardial k) and remodelling (increased volume intercept of diastolic pressure-volume relations) in LV hypertrophy (LVH) is associated with alterations in myocardial collagen cross-linking. METHODS: We evaluated myocardial collagen content (hydroxyproline concentrations [HPRO]) and the degree of myocardial collagen cross-linking (solubility to cyanogen bromide digestion) in 14-15- and 21-22-month-old spontaneously hypertensive rats (SHRs), and in aortic-banded rats with pressure overload hypertrophy (POH). RESULTS: In rats with POH and in SHRs irrespective of age, increases in myocardial [HPRO] were noted. However, hypertensive rats differed in the material and geometric properties of the myocardium, and in qualitative aspects of fibrosis. In 14-15-month-old SHRs myocardial k (determined from diastolic stress-strain relations) and insoluble (cross-linked) [HPRO] were increased, but no LV remodelling or increases in myocardial soluble (non-cross-linked) [HPRO] were noted. In rats with POH, LV remodelling and increases in soluble myocardial [HPRO] occurred, but no increase in k or insoluble myocardial [HPRO] were observed. In 21-22-month-old SHRs, increases in k, soluble and insoluble myocardial [HPRO], as well as LV remodelling occurred. CONCLUSIONS: Collagen cross-linking may determine the diverse relation that exists between increases in myocardial collagen concentrations and either myocardial stiffness or chamber remodelling in hypertension. These findings support the notion that fibrosis contributes to myocardial stiffness as well as LV dilatation in LVH, albeit an effect that is modulated by collagen quality.

Impact of gender and menopausal status on relationships between biological aging, as indexed by telomere length, and aortic stiffness.

BACKGROUND: Telomere length predicts cardiovascular disease (CVD) possibly through an impact of telomere attrition on aortic stiffness. Whether reduced biological aging and a lack of telomere length-aortic stiffness relationships in women contribute to the lower prevalence of CVD in women, prior to menopause, is uncertain. METHODS: We evaluated the relationship between telomere length and carotid-femoral (aortic) pulse wave velocity (PWV) in 580 randomly recruited participants of Black African descent (age = 44 ± 19 years; women: n = 361; premenopausal: n = 195). PWV was determined using carotid and femoral applanation tonometry (SphygmoCor). Relative leukocyte telomere length (T/S) was measured using quantitative real-time polymerase chain reaction assays. RESULTS: Men and women had similar T/S. T/S was inversely correlated with age (r = -0.14, P < 0.001) and this association was similar in all (r = -0.14, P < 0.01) and premenopausal (r = -0.17, P < 0.05) women as in men (r = -0.14, P < 0.05). An inverse relationship between T/S and PWV was noted both before (r = -0.20, P < 0.0001) and after (partial r = -0.14, P < 0.001) adjustments for confounders. No interaction between T/S and either sex or menopausal status was independently associated with PWV, and T/S was independently correlated with PWV in all (partial r = -0.14, P < 0.01) and premenopausal (partial r = -0.18, P < 0.05) women and in men (partial r = -0.15, P < 0.05). CONCLUSIONS: Gender and premenopausal status do not affect age-related decreases in T/S and associations between T/S and PWV. In participants of African descent in whom telomere length did not differ by gender, the impact of gender prior to menopause on CVD is unlikely to be attributed to differences in the effect of biological aging on aortic stiffness.

Intrafamilial aggregation and heritability of left ventricular geometric remodeling is independent of cardiac mass in families of African ancestry.

BACKGROUND: Whether left ventricular (LV) geometric remodeling, as indexed by relative wall thickness (RWT), aggregates in families and is inherited independent of LV mass (LVM) and additional confounders is uncertain. METHODS: We determined whether RWT as assessed from 2D targeted M-mode echocardiography shows intrafamilial aggregation and heritability independent of LVM in 181 nuclear families (73 spouse pairs, 403 parent-child pairs, and 177 sibling-sibling pairs) with 16 families including 3 generations from an urban developing community of black Africans. Intrafamilial aggregation and heritability estimates (S.A.G.E. software) were assessed independent of confounders, including central aortic systolic blood pressure (SBPc) (radial applanation tonometry and SphygmoCor software). RESULTS: Independent of confounders including SBPc, LV RWT was correlated in parent-child (r = 0.32, P < 0.0001) and sibling-sibling (r = 0.29, P < 0.0001), but not in spouse (r = 0.11, P = 0.33) pairs. The relationships between parent-child (r = 0.28, P < 0.0001) and sibling-sibling (r = 0.24, P < 0.001) pairs persisted with further adjustments for LVM or LVM indexed to height(2.7) (LVMI). Similarly, independent of confounders, LV RWT showed significant heritability (h(2) ± SEM = 0.56 ± 0.09, P < 0.0001) and this persisted with further adjustments for LVM (h(2) ± SEM = 0.48 ± 0.09, P < 0.0001) or LVMI (h(2) ± SEM = 0.49 ± 0.09, P < 0.0001). CONCLUSIONS: In a group of African ancestry, independent of LVM, LV geometric remodeling shows significant intrafamilial aggregation and heritability. Genetic factors may in-part determine the LV geometric remodeling process independent of the extent of cardiac hypertrophy.

Impact of renin-angiotensin-aldosterone system gene variants on the severity of hypertension in patients with newly diagnosed hypertension.

BACKGROUND: The severity of hypertension has prognostic significance. Previous studies have assessed the relationship between renin-angiotensin-aldosterone system (RAAS) genotype and the severity of hypertension in either treated patients or those who have only recently discontinued treatment. METHODS: We assessed the impact of RAAS genotype on ambulatory and office blood pressure (BP) in 231 newly diagnosed hypertensive patients of African ancestry who had never received therapy. Subjects were genotyped for variants of the angiotensin-converting enzyme (insertion/deletion), angiotensinogen (M235T, -20A-->C), and aldosterone synthase (CYP11B2)(-344C-->T) genes. RESULTS: The CYP11B2 gene polymorphism was associated with systolic BP (SBP). In comparison to subjects with at least one copy of the -344C allele (n = 75), patients who were homozygous for the -344T allele (n = 156) had both higher ambulatory SBP (150 +/- 1 v 144 +/- 1 mm Hg, P =.002 before and P =.01 after adjusting for multiple genotyping) and office SBP (163 +/- 2 v 156 +/- 2 mm Hg, P =.01 before and P =.05 after adjusting for multiple genotyping). Neither the angiotensin-converting enzyme insertion/deletion nor the angiotensinogen gene polymorphisms were associated with ambulatory or office SBP or diastolic BP (DBP). The CYP11B2 gene variant also did not affect DBP. CONCLUSION: A variant within the CYP11B2 locus has a clinically important impact on the severity of SBP changes in individuals with newly diagnosed hypertension who are of African ethnicity.

Relationship between average leucocyte telomere length and the presence or severity of idiopathic dilated cardiomyopathy in black Africans.

AIMS: A reduced average leucocyte telomere length is associated with ischaemic heart failure. Whether this relationship represents a cause or consequence of heart failure or is attributed to associated risk factors and coronary artery disease is uncertain. We evaluated if average leucocyte telomere length is associated with idiopathic dilated cardiomyopathy (IDC) or its severity. METHODS AND RESULTS: We compared average leucocyte telomere length in 223 patients with heart failure due to IDC and 227 healthy controls of black African ancestry. We also evaluated the relationship between average leucocyte telomere length and left ventricular ejection fraction (LVEF). LVEF was determined using echocardiography and radionuclide multiple-gated acquisition (MUGA) scan in patients with IDC. Relative leucocyte telomere length (T/S) was measured using a quantitative real-time polymerase chain reaction assay. Log T/S was negatively correlated with age in patients with IDC (P = 0.0007) and in controls (P = 0.030), and with alcohol consumption (P = 0.032) and regular smoking (P = 0.021) in patients with IDC. Log T/S did not differ between IDC and control groups either before (P = 0.11) or after (IDC = 0.071 ± 0.187, control = 0.071 ± 0.187, P = 0.99) adjustments for confounders. Log T/S was not associated with echocardiographic (P = 0.47) or MUGA (P = 0.99) LVEF or LV end-diastolic diameter (LVEDD) (P = 0.34) in patients with IDC. With adjustments for age, sex, alcohol consumption, and smoking, log T/S was similarly not associated with echocardiographic (P = 0.60) or MUGA (P = 0.91) LVEF or LVEDD (P = 0.53) in patients with IDC. CONCLUSIONS: Average relative leucocyte telomere length is not associated with IDC or its severity in groups of black African ancestry.

Isolated increases in in-office pressure account for a significant proportion of nurse-derived blood pressure-target organ relations.

AIMS: We determined the extent to which relationships between nurse-derived blood pressures (BPs) and cardiovascular damage may be attributed to isolated increases in in-office SBP independent of ambulatory BP. METHODS: In 750 participants from a community sample, nurse-derived office BP, ambulatory BP, carotid-femoral pulse wave velocity (PWV; applanation tonometry and SphygmoCor software; n=662), and left ventricular mass indexed to height (LVMI; echocardiography; n=463) were determined. RESULTS: Nurse-derived office BP was associated with organ changes independent of 24-h BP (LVMI; partial r=0.15, P<0.005, PWV; partial r=0.21, P<0.0001) and day BP. However, in both unadjusted (P<0.0001 for both) and multivariate adjusted models (including adjustments for 24-h BP; LVMI; partial r=0.14, P<0.01, PWV; partial r=0.21, P<0.0001), nurse office-day SBP (an index of isolated increases in in-office BP) was associated with target organ changes independent of ambulatory BP and additional confounders, with the highest quartile (≥15 mmHg) showing the most marked increases in LVMI (P<0.0005) and PWV (P<0.0001) as compared to the lowest quartile (<-5 mmHg). These relationships were reproduced in those with normotensive day BP values and the quantitative effect of nurse office-day BP on target organ changes was at least equivalent to that of ambulatory BP. CONCLUSION: Nurse-elicited isolated increases in in-office BP account for a significant proportion of the relationship between nurse-derived BP and target organ changes independent of ambulatory BP. Therefore, high quality nurse-derived BP measurements do not approximate the impact of BP effects per se on cardiovascular damage.

Relations between white coat effects and left ventricular mass index or arterial stiffness: role of nocturnal blood pressure dipping.

BACKGROUND: Whether independent relationships between white coat effects (office minus day (office-day blood pressure (BP))) and organ damage or arterial stiffness may be explained by associations with an attenuated nocturnal BP dipping, has not been determined. METHODS: In 750 participants from a sample of African ancestry, office and 24-hour BP, carotid-femoral pulse wave velocity (PWV) (applanation tonometry and SphygmoCor software) (n = 662), and left ventricular mass indexed to height(2.7) (LVMI) (echocardiography) (n = 463) were determined. RESULTS: Office-day systolic BP (SBP) was correlated with day minus night (day-night) SBP, percentage night divided by day (night/day) SBP, and night SBP (P < 0.0005), and these relationships persisted with adjustments for confounders, including day SBP (P < 0.005). With adjustments for 24-hour SBP and additional confounders, office-day SBP was associated with LVMI (P < 0.01) and PWV (P < 0.0001). With adjustments for day SBP and additional confounders, day-night SBP, percentage night/day SBP, and night SBP were related to PWV (P < 0.05) but not to LVMI (P > 0.44). The relationships between office-day SBP and LVMI or PWV persisted with adjustments for either day-night or percentage night/day SBP (LVMI: P = 0.01; PWV: P < 0.0001) or night SBP (LVMI: P < 0.01; PWV: P = 0.0001), and in product of coefficient mediation analysis with appropriate adjustments, neither indexes of nocturnal BP dipping nor nocturnal BP per se contributed toward the impact of office-day BP on LVMI or PWV (P > 0.09). CONCLUSIONS: In a group of African ancestry, although white coat effects are independently associated with an attenuated nocturnal decrease in SBP, neither decreased BP dipping nor nocturnal BP contribute toward the independent relationships between white coat effects and LVMI or arterial stiffness.