Eating and arterial endothelial function: a meta-analysis of the acute effects of meal consumption on flow-mediated dilation.

Given that endothelial dysfunction precedes atherosclerotic cardiovascular disease, exploring the parameters that modify postprandial flow-mediated dilation (FMD) is important for public health. The objectives of the study are to estimate the population effect of meal ingestion on FMD and to determine how the effect varied based on patient characteristics and modifiable methodological features. Articles published before June 2015 were located using MEDLINE, PubMed and Web of Science. One hundred fifty-four effects were derived from 78 articles involving 2,548 subjects were selected. Included articles required measurement of FMD in adults before and after meal ingestion. Effects were analysed using an unstandardized mean gain random effects model, and significant moderators were analysed using meta-regression. Meal consumption significantly reduced FMD by a heterogeneous mean effect size delta (Δ) of -2.03 (95% CI: [-2.28, -1.77]), an ~2% reduction in FMD. FMD reductions were larger among normal weight individuals, males, those with a cardio-metabolic disorder, those with elevated baseline FMD, and individuals with impaired glucose tolerance at baseline. Macronutrient meal ingestion significantly reduced FMD, an effect that was moderated by body mass index, sex and two-way interactions between disease status and both baseline FMD and baseline blood glucose levels.

Estrogen replacement therapy improves baroreflex regulation of vascular sympathetic outflow in postmenopausal women.

BACKGROUND: Menopausal estrogen loss has been associated with increased cardiovascular disease in postmenopausal women. However, the link between estrogen and cardiovascular disease remains unclear. Some data suggest estrogen mediates its effect through changes in arterial pressure and its regulation. However, the data available in older women are equivocal regarding estrogen's ability to reduce resting arterial pressure or to improve its regulation. METHODS AND RESULTS: We studied 11 healthy, postmenopausal women before and after 6 months of estrogen administration. Arterial pressure was measured by brachial auscultation and finger photoplethysmography. Vascular sympathetic nerve activity was measured in the peroneal nerve by microneurography, and the slope of the relations between changes in heart period, sympathetic activity, and arterial pressure caused by bolus infusions of nitroprusside and phenylephrine were used as an index of baroreflex gain. Estrogen therapy did not change systolic pressure (128+/-2 versus 123+/-2 mm Hg) or cardiac-vagal baroreflex gain (6.6+/-0.9 versus 6.7+/-0.7 ms/mm Hg). However, vascular sympathetic baroreflex gain was increased (-4.6+/-0.6 versus -7.4+/-1.0 arbitrary integrated units/mm Hg; P=0.02). CONCLUSION: These findings suggest long-term estrogen replacement therapy has effects on cardiovascular regulation that may not be reflected in resting arterial pressures.

Quantification of mechanical and neural components of vagal baroreflex in humans.

Traditionally, arterial baroreflex control of vagal neural outflow is quantified by heart period responses to falling and/or rising arterial pressures (ms/mm Hg). However, it is arterial pressure-dependent stretch of barosensory vessels that determines afferent baroreceptor responses, which, in turn, generate appropriate efferent cardiac vagal outflow. Thus, mechanical transduction of pressure into barosensory vessel stretch and neural transduction of stretch into vagal outflow are key steps in baroreflex regulation that determine the conventional integrated input-output relation. We developed a novel technique for direct estimation of gain in both mechanical and neural components of integrated cardiac vagal baroreflex control. Concurrent, beat-by-beat measures of arterial pressures (Finapres), carotid diameters (B-mode ultrasonography), and R-R intervals (ECG lead II) were made during bolus vasoactive drug infusions (modified Oxford technique) in 16 healthy humans. The systolic carotid diameter/pressure relationship (r(2)=0.79+/-0.008, mean+/-SEM) provided a gain estimate of dynamic mechanical transduction of pressure into a baroreflex stimulus. The R-R interval/systolic diameter relationship (r(2)=0.77+/-0.009) provided a gain estimate of afferent-efferent neural transduction of baroreflex stimulus into a vagal response. Variance between repeated measures for both estimates was no different than that for standard gain (P>0.40). Moreover, in these subjects, the simple product of the 2 estimates almost equaled standard baroreflex gain (ms/mm Hg=0.98x+2.27; r(2)=0.93, P=0.001). This technique provides reliable information on key baroreflex components not distinguished by standard assessments and gives insight to dynamic mechanical and neural events during acute changes in arterial pressure.

Does reduced vascular stiffening fully explain preserved cardiovagal baroreflex function in older, physically active men?

BACKGROUND: We measured cardiovagal baroreflex gain and its vascular mechanical and neural components during dynamic baroreflex engagement in 10 young untrained men, 6 older untrained men, and 12 older, physically active men. METHODS AND RESULTS: Our newly developed assessment of beat-to-beat carotid diameters during baroreflex engagement estimates the mechanical transduction of pressure into barosensory stretch (diameter/pressure), the neural transduction of stretch into vagal outflow (R-R interval/diameter), and conventional integrated cardiovagal baroreflex gain (R-R interval/pressure). Integrated gain was lower in older untrained men than in young untrained men (6.8+/-1.2 versus 15.7+/-1.8 ms/mm Hg) due to both lower mechanical (9.1+/-1.0 versus 17.1+/-2.4 mm Hg/microm) and lower neural (0.57+/-0.10 versus 0.90+/-0.10 ms/microm) transduction. Integrated gain in older active men (13.3+/-2.7 ms/mm Hg) was comparable to that in young untrained men. This was achieved through mechanical transduction (12.1+/-1.4 mm Hg/microm) that was modestly higher than that in older untrained men and neural transduction (1.00+/-0.20 ms/microm) comparable to that in young untrained men. Across groups, both mechanical and neural components were related to integrated gain; however, the neural component carried greater predictive weight (beta=0.789 versus 0.588). CONCLUSIONS: Both vascular and neural deficits contribute to age-related declines in cardiovagal baroreflex gain; however, long-term physical activity attenuates this decline by maintaining neural vagal control.

Hemodynamic sequelae of age-related increases in arterial stiffness in healthy women.

Stiffening of central arteries is believed to contribute to the increase in the incidence of cardiovascular disease with age, presumably through its adverse influence on arterial blood pressure. We found that (1) the physiologic link between age-related increases in arterial stiffness and blood pressure appears to be elevated systemic vascular resistance, and (2) increased arterial stiffness and systemic vascular resistance with age were inversely related to blood volume, stroke volume, and cardiac output.

Role of central circulatory factors in the fat-free mass-maximal aerobic capacity relation across age.

Fat-free mass (FFM) (primarily skeletal muscle mass) is related to maximal aerobic capacity among healthy humans across the adult age range. The basis for this physiological association is assumed to be a direct relation between skeletal muscle mass and its capacity to consume oxygen. We tested the alternative hypothesis that FFM exerts its influence on maximal aerobic capacity in part via an association with central circulatory function. To do so, we analyzed data from 103 healthy sedentary adults aged 18-75 yr. FFM was strongly and positively related to maximal oxygen consumption (r = 0.80, P < 0. 001). FFM was also strongly and positively related to supine resting levels of blood volume (r = 0.79, P < 0.001) and stroke volume (r = 0.75, P < 0.001). Statistically controlling for the collective influences of blood volume and stroke volume abolished the tight relation between FFM and maximal oxygen consumption (r = 0.12, not significant). These results indicate that 1) FFM may be an important physiological determinant of blood volume and stroke volume among healthy sedentary adult humans of varying age; and 2) this relation between FFM and central circulatory function appears to represent the primary physiological basis for the strong association between FFM and maximal aerobic capacity in this population. Our findings suggest that sarcopenia (loss of skeletal muscle mass with aging) may contribute to the age-related decline in maximal aerobic capacity primarily via reductions in blood volume and stroke volume rather than a direct effect on the oxygen-consuming potential of muscle per se.

Reproducibility of a semiautomated acetylene rebreathing technique for measuring cardiac output in humans at rest.

The specific aims of the present study were to determine: (1) the day-to-day reproducibility of a semiautomated acetylene rebreathing technique for measuring cardiac output under resting conditions; (2) the reproducibility of this technique among subjects differing in gender and age; and (3) the number of trials within a session necessary to maximize the day-to-day reproducibility of the technique. To address these aims, cardiac output was measured in 21 healthy men (n = 8) and women (n = 13) between the ages of 25 and 71 years in the supine posture on two separate days. Mean levels of cardiac output at rest were similar on day 1 vs. day 2 in the overall group. Cardiac output measured on day 1 was highly correlated (r = 0.98, P < 0.001) with cardiac output measured on day 2. The day 1 to day 2 mean difference in cardiac output for the individual subjects was < 4%. The mean levels of heart rate and stroke volume also were similar between day 1 and day 2. The relation between cardiac output measured on day 1 vs. day 2 in the gender and age subgroups was similar to that observed in the overall group. The mean absolute difference among the three rebreathing trials within a day was 360 ml min-1 in the overall group, with a coefficient of variation of 7%. The variability between rebreathing trials measured on day 1 vs. day 2 in the gender and age subgroups was similar to that observed in the overall group. The reliability of cardiac output measured on different days was excellent with a single rebreathing trial (r = 0.93) and improved significantly up to three trials (r = 0.98). In conclusion, the findings of the present study indicate that the acetylene rebreathing technique can be a highly reproducible method for measuring cardiac output under resting conditions. The reproducibility is consistently strong in healthy humans of varying age and in both genders, and is enhanced by the use of multiple trials.

Systemic hemodynamic determinants of blood pressure in women: age, physical activity, and hormone replacement.

We tested the hypothesis that the age-related changes in systemic hemodynamic determinants of arterial blood pressure in healthy women are related to physical activity and hormone replacement status. We studied 66 healthy, normotensive premenopausal (21-35 yr) and postmenopausal (50-72 yr) sedentary and endurance-trained women under supine resting conditions. Mean blood pressure was 7 mmHg higher in sedentary post- compared with premenopausal women, which was associated with an 11-mmHg higher systolic blood pressure, a 25% lower stroke volume and cardiac output, and a 50% higher systemic vascular resistance (all P < 0.05). Absolute (ml) levels of total blood volume did not differ across age, but resting oxygen consumption was approximately 35% lower in the postmenopausal women (P < 0.05). The elevations in mean and systolic blood pressures with age were similar in endurance-trained runners, but, in contrast to the sedentary women, the elevations were not associated with significant age-related differences in cardiac output, stroke volume, or oxygen consumption, and only a modest (15%) increase in systemic vascular resistance (P = 0.06). Postmenopausal swimmers demonstrated the same systemic hemodynamic profile as that of postmenopausal runners, indicating a nonspecific influence of the endurance-trained state. Blood pressure and its systemic hemodynamic determinants did not differ in postmenopausal users compared with those of nonusers of hormone replacement therapy. Resting oxygen consumption was the strongest physiological correlate of cardiac output in the overall population (r = 0.65, P < 0.001). We conclude that 1) the increases in arterial blood pressure at rest with age in healthy normotensive women are not obviously related to habitual physical activity status; 2) the systemic hemodynamic determinants of the age-related elevations in blood pressure are fundamentally different in sedentary vs. active women, possibly due, in part, to an absence of decline in resting oxygen consumption in the latter; and 3) systemic hemodynamics at rest are not different in healthy normotensive postmenopausal users vs. nonusers of estrogen-based hormone replacement.

kurkku, a Phenotype of Acetabularia acetabulum That Is Arrested in Vegetative Growth, Can Be Rescued with Wild-Type Cytoplasm.

We isolated several spontaneous phenotypes in the giant unicell Acetabularia acetabulum that have vegetative terminal morphologies. Because they arrest in vegetative development, these cell lines are effectively immortalized. However, they had to be rescued before they could be studied via classical genetics because no heterozygotes from the original self-crosses were found, that is, the wild-type siblings yielded only wild-type progeny. We attempted to rescue these phenotypes in three ways: by amputating the cell apex, by "piggybacking" the mutant nucleus through development in a binucleate heterokaryon, and by replacing the abnormal apex with a wild-type apex. We used one of our immortal cell lines, kurkku, which has a terminal phenotype consistent with arrest early in the juvenile phase of vegetative development, as a prototype for these rescue methods. The kurkku phenotype segregated 1:3 in the original self-cross in which it arose as if it were a single, recessive Mendelian trait. Although amputation failed to rescue kurkku, we succeeded in compensating for the defect both in binucleate heterokaryons and in apical grafts to wild-type cells. kurkku was always recovered in the progeny of the self-crosses of these grafts. These unique ways of analyzing vegetative mutants, combined with the ability to then perform classical genetics, may make A. acetabulum a powerful unicellular model system for the study of vegetative phase change in plants.

Macromolecular mechanisms of sputum inhibition of tobramycin activity.

Tobramycin, an aminoglycoside antibiotic, is used in the treatment of Pseudomonas aeruginosa infections in cystic fibrosis patients. Tobramycin bioactivity, however, is antagonized by sputum. Glycoproteins (mucins) and high-molecular-weight DNA make up 2 to 3% (P. L. Masson and J. F. Heremans, p. 412-475, In M. J. Dulfano, ed., Sputum: Fundamentals and Clinical Pathology, 1973) and 3 to 10% (W. S. Chernick and G. J. Barbero, Pediatrics 24:739-745, 1959, and R. Picot, I. Das, and L. Reid, Thorax 33:235-242, 1978) of the dry weight of sputum, respectively. tobramycin binds to both mucins and DNA obtained from sputum (R. Ramphal, M. Lhermitte, M. Filliat, and P. Roussel, J. Antimicrob. Chemother. 22:483-490, 1988). In vitro, recombinant human DNase (rhDNase) hydrolyzes high-molecular-weight DNA of > 50 kb within sputum to fragments of 2 to 4 kb. Studying dialyzable tobramycin, we examined drug binding to whole sputum and to "mock sputum," which consisted of porcine gastric mucin and calf thymus DNA. We also studied the effects of rhDNase treatments of sputum, mock sputum, and calf thymus DNA on tobramycin binding. We found that treatments of sputum, mock sputum, and calf thymus DNA with rhDNase did not significantly increase the tobramycin bioactivity within the dialysates; surprisingly, sputum binding of tobramycin was increased by rhDNase. We conclude that rhDNase does not increase the bioactivity of tobramycin in sputum.