Christoph D. Gatzka

Muscular Strength Training Is Associated With Low Arterial Compliance and High Pulse Pressure

Aerobic exercise training increases arterial compliance and reduces systolic blood pressure, but the effects of muscular strength training on arterial mechanical properties are unknown. We compared blood pressure, whole body arterial compliance, aortic impedance, aortic stiffness (measured by beta-index and carotid pulse pressure divided by normalized systolic expansion [Ep]), pulse wave velocity, and left ventricular parameters in 19 muscular strength-trained athletes (mean+/-SD age, 26+/-4 years) and 19 sedentary controls (26+/-5 years). Subjects were healthy, non-steroid-using, nonsmoking males, and athletes had been engaged in a strength-training program with no aerobic component for a minimum of 12 months. There was no difference in maximum oxygen consumption between groups, but handgrip strength (mean+/-SEM, 44+/-2 versus 56+/-2 kg; P<0.01) and left ventricular mass (168+/-8 versus 190+/-8 g; P<0.05) were greater in athletes. Arterial stiffness was higher in athletes, as evidenced by lower whole body arterial compliance (0.40+/-0.04 versus 0.54+/-0.04 arbitrary compliance units; P=0.01), higher aortic characteristic impedance (1.55+/-0.13 versus 1.18+/-0.08 mm Hg. s. cm-1; P<0.05), beta-index (4.6+/-0.2 versus 3.8+/-0.4; P<0. 05), and ln Ep (10.86+/-0.06 versus 10.60+/-0.08; P<0.01). Femoral-dorsalis pedis pulse wave velocity was also higher in the athletes, but carotid-femoral pulse wave velocity was not different. Furthermore, both carotid (56+/-3 versus 44+/-2 mm Hg; P<0.001) and brachial (60+/-3 versus 50+/-2 mm Hg; P<0.01) pulse pressures were higher in the athletes, but mean arterial pressure and resting heart rate did not differ between groups. These data indicate that both the proximal aorta and the leg arteries are stiffer in strength-trained individuals and contribute to a higher cardiac afterload.

Relation Between Coronary Artery Disease, Aortic Stiffness, and Left Ventricular Structure in a Population Sample

To elucidate the relationship between coronary artery disease (CAD), aortic stiffness, and left ventricular structure, we recruited 55 subjects (33 men; average age, 63+/-1 years) with previously unknown CAD from a healthy general population sample, as well as 55 control subjects matched for gender, age, and serum cholesterol level. We measured arterial blood pressure and the systolic expansion of the transverse aorta and left ventricular structure by echocardiography. Aortic stiffness was higher in CAD patients than in controls, with a brachial pulse pressure of 59+/-3 versus 52+/-2 mm Hg and stiffness indices of Ep=212+/-26 versus 123+/-13 kN/m2 and beat=16+/-2 versus 9+/-1 (all P<0.01). Mean arterial pressure was similar in both groups during the measurements (95+/-2 versus 93+/-2 mm Hg, P=NS). Most CAD patients (61%) were in the highest stiffness quartile defined by the normal control values (P<0.05 versus control). Left ventricular mass index was also higher in CAD patients than in matched controls (139+/-5 versus 123+/-4 g/m2, P<0.05). We conclude that aortic stiffness and left ventricular mass are increased in subjects newly diagnosed as having CAD. This might explain previously reported associations of an increased mortality, particularly from CAD, found among subjects with elevated pulse pressures.

Aerobic Exercise Training Does Not Modify Large-Artery Compliance in Isolated Systolic Hypertension

The present study characterized large-artery properties in patients with isolated systolic hypertension (ISH) and determined the efficacy of exercise training in modifying these properties. Twenty patients (10 male and 10 female) with stage I ISH and 20 age- and gender-matched control subjects were recruited, and large-artery properties were assessed noninvasively. Ten ISH patients (5 male and 5 female) were enrolled in a randomized crossover study comparing 8 weeks of moderate intensity cycling with 8 weeks of sedentary activity. Brachial and carotid systolic, diastolic, mean, and pulse pressures were higher in the ISH group than in the control group. Systemic arterial compliance (0.43±0.04 versus 0.29±0.02 arbitrary compliance units for the control versus ISH groups, respectively;P =0.01) was lower, and carotid-to-femoral pulse-wave velocity (9.67±0.36 versus 11.43±0.51 m · s−1 for the control versus ISH groups, respectively;P =0.007), input impedance (2.39±0.19 versus 3.27±0.34 mm Hg · s · cm−1 for the control versus ISH groups, respectively;P =0.04), and characteristic impedance (1.67±0.17 versus 2.34±0.27 mm Hg · s · cm−1 for the control versus ISH groups, respectively;P =0.05) were higher in the ISH group than in the control group. Training increased maximal oxygen consumption by 13±5% (P =0.04) and maximum workload by 8±4% (P =0.05); however, there was no effect on arterial mechanical properties, blood lipids, or left ventricular mass or function. These results suggest that the large-artery stiffening associated with ISH is resistant to modification through short-term aerobic training.

Matrix Metalloproteinase-3 Genotype Contributes to Age-Related Aortic Stiffening Through Modulation of Gene and Protein Expression

Abstract —Matrix metalloproteinases (MMPs) include most major constituents of the arterial wall as substrates. A common promotor polymorphism (5A/6A) is associated with differences in MMP‐3 (stromelysin‐1) activity, and associations with certain forms of vascular disease have been shown. This study investigated whether the MMP‐3 5A/6A promoter polymorphism contributes to age‐related large artery stiffening. MMP‐3 5A/6A genotype was determined in 203 (135 male) low cardiovascular risk, unmedicated individuals who were divided prospectively into two groups (30 to 60 years, n=126; ≥61 years, n=77). Noninvasive large artery stiffness was measured as ascending aortic input impedance from brachial blood pressure, carotid tonometry, and Doppler ascending aortic blood flow. In the older group, homozygotes had higher aortic input (P<0.01) and characteristic (P<0.01) impedance, ie, higher stiffness, than heterozygotes after correction for the effects of age, gender, and mean arterial pressure. There was no such difference in the younger group. Gene expression was subsequently investigated in dermal biopsies in randomly selected older men from the same cohort with real‐time PCR (n=40). In 5A homozygotes, gene expression was 4‐fold higher (P<0.05), and in 6A homozygotes, 2‐fold lower (P<0.05) compared with the heterozygotes. Differences in gene expression were associated with corresponding significant changes in MMP‐3 protein levels. Concordance between dermal and aortic gene and protein expression was shown in a separate cohort of postmortem aortic samples (n=7). We conclude that MMP‐3 genotype may be an important determinant of vascular remodeling and age‐related arterial stiffening, with the heterozygote having the optimal balance between matrix accumulation and deposition. (Circ Res. 2003;92:1254–1261.)

Gender differences in the timing of arterial wave reflection beyond differences in body height.

Objectives The timing of arterial wave reflection affects the shape of the arterial waveform and thus is a major determinant of pulse pressure. This study assessed differences in wave reflection between genders beyond the effect of body height. Methods From 1123 elderly (aged 71 ± 5 years) currently untreated hypertensives, we selected 104 pairs of men and women with identical body height (average 164 ± 4 cm). All subjects underwent echocardiography, including measurement of aortic arch expansion, automated blood pressure measurements, measurement of ascending aortic blood flow and simultaneous carotid artery tonometry. Results Women had higher pulse (80 ± 17 versus 74 ± 17 mmHg, P < 0.05) and lower diastolic pressure (79 ± 11 versus 82 ± 10 mmHg, P < 0.05). Whilst heart rate was similar, women had a longer time to the systolic peak (210 ± 28 versus 199 ± 34 ms, P < 0.01) and a longer ejection time (304 ± 21 versus 299 ± 25 ms, P < 0.001). Wave reflection occurred earlier in women (time between maxima 116 ± 55 versus 132 ± 47 ms, P < 0.05) and augmentation index was higher (36 ± 11 versus 28 ± 12%, P < 0.001). Aortic diameter was smaller in women and the aortic arch was stiffer (median Ep 386 versus 302 kN/m2, P < 0.05). Hence, systemic arterial compliance was less in women (0.8 ± 0.2 versus 1.0 ± 0.3 ml/mmHg). Conclusions We conclude that elderly hypertensive men and women have a different timing of both left ventricular ejection and arterial wave reflection when both genders are matched for body height. Women have smaller and stiffer blood vessels resulting in an earlier return of the reflected wave, which is likely due to an increased pulse wave velocity in women.

Women exhibit a greater age-related increase in proximal aortic stiffness than men.

Background Large artery mechanical properties are a major determinant of pulse pressure and cardiovascular outcome. Sex differences in these properties may underlie the variation in cardiovascular risk profile between men and women, in relation to age. Objective To investigate sex differences in the age-related stiffening of large arteries. Design Cross-sectional. Methods One hundred and twenty healthy men and women were recruited and divided equally into tertiles by age: young (mean ± SD, 23 ± 5 years), middle-age (47 ± 3 years) and older (62 ± 7 years). Lipids, mean arterial pressure and heart rate were matched within each tertile. Carotid tonometry and Doppler velocimetry were used to measure indices of large artery stiffness. Results There was no sex difference in systemic arterial compliance (SAC) in the young group (mean ± SEM, 0.61 ± 0.05 arbitrary compliance units (ACU) in women compared with 0.67 ± 0.04 ACU in men), but in the older population women had lower SAC than men (0.27 ± 0.03 ACU compared with 0.57 ± 0.04 ACU respectively;P < 0.001). Measures independent of aortic geometry (distensibility index and aortic impedance) indicated that stiffness was lower in young women than in men (P < 0.05), but the reverse was true in the older population (P < 0.01). This paralleled the brachial and carotid pulse pressures, which were lower in young (P < 0.01) and higher in older women compared with those in men (P < 0.05). Follicle stimulating hormone concentrations correlated strongly (r values 0.39–0.65) with all indices of central, but not peripheral, arterial function, whereas concentrations of luteinizing hormone, progesterone and oestradiol correlated less strongly. Conclusions In men and women matched for mean pressures, the age-related stiffening of large arteries is more pronounced in women, which is consistent with changes in female hormonal status.

Matrix Metalloproteinase-9 Genotype Influences Large Artery Stiffness Through Effects on Aortic Gene and Protein Expression

Objective—Because large artery stiffening contributes to myocardial ischemia, its determinants are of relevance as potential risk markers. This study examined whether matrix metalloproteinase (MMP)-9 (gelatinase B) genotype is associated with large artery stiffening and aortic MMP-9 gene and protein expression. Methods and Results—MMP-9 genotype (C-1562T promoter polymorphism) was determined in 84 patients (73 male) with angiographically defined coronary artery disease (CAD). Carotid applanation tonometry was used to assess central blood pressures and, with Doppler velocimetry, to assess aortic stiffness (input and characteristic impedance). Gene expression real-time polymerase chain reaction (RT-PCR) and protein levels (Western blotting) were assessed in relation to genotype in aortic samples from a separate population. T-allele carriers (C/T and T/T) had stiffer large arteries (higher input and characteristic impedance) and higher carotid pulse and systolic blood pressure (all P <0.05) than C/C homozygotes. In aortic samples, gene expression was 5-fold higher and active protein levels were >2-fold higher in T-allele carriers. Conclusions—Because the T allele was associated with greater MMP-9 mRNA and protein levels, the greater large artery stiffness in T-allele carriers may be secondary to excessive degradation of the arterial elastic matrix. The consequent higher pulse pressure may increase susceptibility to myocardial ischemia.

Correction of carotid augmentation index for heart rate in elderly essential hypertensives

Carotid augmentation index (AI) is used as a surrogate measure of arterial stiffness. Although arterial stiffness has been shown to either remain unchanged or increase with an increase in heart rate, AI decreases as heart rate increases. This study aimed to quantify this confounding effect of heart rate on AI. We investigated 873 hypertensives, mean age 72 +/- 5 years, 44% men, mean brachial blood pressure 161 +/- 21/82 +/- 11 mm Hg. Carotid artery tonometry with simultaneous continuous wave Doppler measurement of ascending aortic blood flow was performed. AI was calculated from the carotid pressure waveform. Waveforms were decomposed into their forward and backward components and the time to reflection between the maxima of the forward and backward pressure waves was measured. AI showed a stronger (P < .001) association with ejection time (r = 0.48, P < .001) than with heart rate (r = -0.28, P < .001). Although AI is strongly related to the time to reflection (r = -0.51, P < .001), only a weak association was seen between time to reflection and heart rate (r = 0.16, P < .001) or ejection time (r = -0.12, P < .001). Our analysis in an elderly cohort of patients with essential hypertension demonstrates that AI is related to the time to reflection. It also reiterates that AI is confounded by heart rate without any underlying heart rate-dependent change in wave reflection. In population-based studies the confounding effect of heart rate can potentially be corrected. AI remains strongly (r = -0.52) related to time to reflection after correction for the effects of ejection time on AI.

Similar Effects of Treatment on Central and Brachial Blood Pressures in Older Hypertensive Subjects in the Second Australian National Blood Pressure Trial

The Second Australian National Blood Pressure Trial reported better prognosis for hypertensive subjects randomly assigned to an angiotensin-converting enzyme inhibitor (ACE-I) compared with a diuretic-based regimen despite no difference in brachial blood pressure control. A possible explanation is that there was a difference in central aortic pressures despite similar brachial pressure reductions. We examined this hypothesis in a subset of the Second Australian National Blood Pressure Trial cohort evaluated both before and after 4 years of treatment. The average age of the 479 subjects was 71.6±4.7 years (mean±SD), and 56% were women. Brachial systolic and pulse pressures after treatment were 145±1 (mean±SEM), 143±1, 72±1, and 70±1 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were −17±2, −16±2, −9±1, and −7±1 mm Hg. None of the differences between diuretic and ACE-I groups were significant. Central arterial pressure waveforms were acquired from carotid tonometry and calibrated from brachial pressures. Central systolic and pulse pressures posttreatment were 144±2, 144±2, 71±2, and 72±2 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were −15±2, −17±2, −6±2, and −8±2 mm Hg. None of the differences between diuretic and ACE-I groups were significant. The similarity of central and brachial pressures in this cohort of older hypertensive subjects is most likely because of the influences of age and hypertension in increasing arterial stiffness. There is no evidence that the better prognosis for patients randomly assigned to ACE-I in Second Australian National Blood Pressure Trial resulted from a disproportionate lowering of central blood pressure.

Large-Artery Stiffness Contributes to the Greater Prevalence of Systolic Hypertension in Elderly Women

Objectives: To determine whether sex differences in large‐artery stiffness contribute to the greater prevalence of systolic hypertension in elderly women than in elderly men.