Richard Brooksbank

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.

Relationship Between Urinary Salt Excretion and Pulse Pressure and Central Aortic Hemodynamics Independent of Steady State Pressure in the General Population

Although central pulse pressure (PPc) is strongly related to central mean arterial pressure (MAPc), PPc predicts cardiovascular outcomes beyond MAPc. Whether modifiable risk factors for hypertension contribute to PPc and its determinants, independent of MAPc, is uncertain. In 635 randomly recruited participants, we assessed the independent relationship between 24-hour urinary sodium (Na+) or potassium (K+) excretion and brachial artery PP (in office or 24-hour; n=487), PPc, the forward (P1) and augmented (Paug) pressure wave components of PPc, central augmentation index, and determinants of central pressure waves, including aortic pulse wave velocity, effective reflecting distance, and reflective wave transit time. Central dynamics were determined using applanation tonometry of the carotid, femoral, and radial arteries. With adjustments for potential confounders, urinary Na+/K+ was independently associated with in-office, central, and 24-hour PP, as well as Paug, P1, and central augmentation index (P<0.05 to P<0.005). With further adjustments for MAPc (or diastolic BP), urinary Na+/K+ was independently associated with PPc, 24-hour PP, Paug, P1, and central augmentation index (P<0.05 to P=0.005) but not with in-office PP, pulse wave velocity, effective reflecting distance, or reflective wave transit time. In conclusion, in a population of African ancestry, urinary salt excretion is independently related to central and 24-hour PP independent of MAPc or diastolic BP, effects that are attributed to increases in both P1 and Paug but not to pulse wave velocity. Hence, modifying salt intake could influence cardiovascular risk through effects on 24-hour and central PPs, as well as P1 and Paug, independent of steady-state pressure (MAP or diastolic BP) or pulse wave velocity.

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.

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.

β-Adrenergic Activation Initiates Chamber Dilatation in Concentric Hypertrophy

Abstract—It is uncertain whether chronic &bgr;-adrenoreceptor (&bgr;-AR)–activation in hypertension could initiate the progression from compensated left ventricular (LV) hypertrophy to pump dysfunction. It is also uncertain if this effect is through adverse LV remodeling (chamber dilatation with wall thinning and pump dysfunction) or intrinsic myocardial contractile dysfunction. We evaluated the effect of 5 months of isoprenaline (0.02 mg · kg−1 · d−1) on hemodynamics, LV wall thickness, cavity size, and interstitial characteristics in spontaneously hypertensive rats (SHR) with compensated LV hypertrophy. In the absence of myocyte necrosis, changes in volume preload, pressure afterload, and heart rate or decreases in baseline systolic myocardial elastance (load independent measure of intrinsic myocardial contractility), ISO produced a right shift in LV diastolic pressure–volume (P-V) relations (chamber dilatation), a decrease in LV wall thickness despite a further increase in LV weight in SHR, LV pump dysfunction (right shift in LV systolic P-V relations), and deleterious interstitial remodeling (increments in total and noncrosslinked myocardial collagen concentrations). The isoprenaline-induced LV geometric, chamber performance, and interstitial changes were similar to alterations noted during decompensation in older SHR. In summary, in the absence of tissue necrosis and baseline intrinsic myocardial contractile dysfunction, chronic &bgr;-AR activation induces interstitial and chamber remodeling and, hence, pump dysfunction. These data suggest that chronic sympathetic activation initiates the progression from compensated concentric LV hypertrophy in hypertension to cardiac dysfunction primarily through deleterious cardiac remodeling rather than intrinsic myocardial contractile dysfunction.

Contribution of Central and General Adiposity to Abnormal Left Ventricular Diastolic Function in a Community Sample With a High Prevalence of Obesity

The relative independent contribution of excess adiposity, as indexed by measures of central, general, or peripheral adiposity, toward abnormal cardiac diastolic chamber function at a community level is unclear. In 377 randomly selected participants >16 years old from a community sample with a high prevalence of excess adiposity ( approximately 25% overweight and approximately 43% obese), we assessed the independent contribution of the indexes of adiposity to the variation in early-to-late (atrial) transmitral velocity (E/A). After adjustments for a number of confounders, including age, gender, pulse rate, conventional diastolic (or systolic) blood pressure, antihypertensive treatment, left ventricular mass index, and the presence of diabetes mellitus or a hemoglobin A1c level >6.1%; waist circumference was an independent predictor of a reduced E/A (p = 0.0038). Body mass index (p = 0.07), waist-to-hip ratio (p = 0.23), and skinfold thickness (p = 0.37) were not independently associated with E/A, whereas waist circumference was independently associated with E/A, even after adjustments for other adiposity indexes, including body mass index (p <0.05 to 0.005). In contrast to the effects on diastolic function, the waist circumference did not correlate with the left ventricular ejection fraction (p = 0.23). The independent relation between the waist circumference and E/A (standardized beta coefficient -0.14 +/- 0.05, p = 0.0038) was second only to age (standardized beta coefficient -0.57 +/- 0.05, p <0.0001) and similar to blood pressure (standardized beta coefficient -0.11 +/- 0.04, p = 0.0075) in the magnitude of the independent effect on E/A. The inclusion of the relative wall thickness rather than the left ventricular mass index in the regression equation produced similar outcomes. The exclusion of the left ventricular mass index and relative wall thickness from the regression equations or the inclusion of carotid-femoral pulse wave velocity or 24-hour blood pressure as confounders failed to modify the relation between waist circumference and E/A. In conclusion, the waist circumference was second only to age in the impact on an independent association with E/A in a population sample with a high prevalence of excess adiposity. This effect was not accounted for by left ventricular hypertrophy or remodeling, the 24-hour blood pressure, or arterial stiffness.

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.

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

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.

Insulin Resistance and the Relationship Between Urinary Na+/K+ and Ambulatory Blood Pressure in a Community of African Ancestry

BACKGROUND Although groups of African descent are particularly sensitive to blood pressure (BP) effects of salt intake, the role of obesity and insulin resistance in mediating this effect is uncertain. We determined whether obesity or insulin resistance is independently associated with urinary Na(+)/K(+)-BP relationships in a community sample of African ancestry. METHODS We measured 24-hour urinary Na(+)/K(+), homeostasis model assessment of insulin resistance (HOMA-IR), and nurse-derived conventional and 24-hour ambulatory BP in 331 participants from a South African community sample of black African descent not receiving treatment for hypertension. RESULTS With adjustments for diabetes mellitus and the individual terms, an interaction between waist circumference and urinary Na(+)/K(+) was associated with day diastolic BP (P < 0.05) and an interaction between log HOMA-IR and urinary Na(+)/K(+) was associated with 24-hour and day systolic (P < 0.05) and 24-hour, day, and night diastolic (P < 0.002; P < 0.001) BP. The multivariable-adjusted relationship between urinary Na(+)/K(+) and night diastolic BP increased across tertiles of HOMA-IR (tertile 1: β-coefficient = -0.79 ± 0.47; tertile 2: β-coefficient = 0.65 ± 0.35; tertile 3: β-coefficient = 1.03 ± 0.46; P < 0.05 tertiles 3 and 2 vs. 1). The partial correlation coefficients for relationships between urinary Na(+)/K(+) and 24-hour (partial r = 0.19; P < 0.02), day (partial r = 0.17; P < 0.05), and night (partial r = 0.18; P < 0.02) diastolic BP in participants with log HOMA-IR greater than or equal to the median were greater than those for relationships between urinary Na(+)/K(+) and 24-hour (partial r = -0.08; P = 0.29), day (partial r = -0.10; P < 0.22), and night (partial r = -0.06; P = 0.40) diastolic BP in participants with log HOMA-IR less than the median (comparisons of r values: P < 0.05). CONCLUSIONS Insulin resistance may modify the relationship between salt intake, indexed by urinary Na(+)/K(+), and ambulatory BP in groups of African descent.