Adipokines and the Right Ventricle: The MESA-RV Study

Objective

Obesity is associated with changes in both right (RV) and left (LV) ventricular morphology, but the biological basis of this finding is not well established. We examined whether adipokine levels were associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease.

Methods

We examined relationships of leptin, resistin, TNF-α, and adiponectin with RV morphology and function (from cardiac MRI) in participants (n = 1,267) free of clinical cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25^th and 75^th] and generalized additive models [GAM]) were used to examine the independent association of each adipokine with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF).

Results

Higher leptin levels were associated with significantly lower levels of RV mass, RVEDV, RVESV and stroke volume, but not RVEF, after adjustment for age, gender, race, height and weight. These associations were somewhat attenuated but still significant after adjustment for traditional risk factors and covariates, and were completely attenuated when correcting for the respective LV measures. There were no significant interactions of age, gender, or race/ethnicity on the relationship between the four adipokines and RV structure or function.

Conclusions

Leptin levels are associated with favorable RV morphology in a multi-ethnic population free of cardiovascular disease, however these associations may be explained by a yet to be understood bi-ventricular process as this association was no longer present after adjustment for LV values. These findings complement the associations previously shown between adipokines and LV structure and function in both healthy and diseased patients. The mechanisms linking adipokines to healthy cardiovascular function require further investigation.     

Right Ventricular Morphology and the Onset of Dyspnea: The MESA-Right Ventricle Study

Background

The association of right ventricular (RV) structure and function with symptoms in individuals without cardiopulmonary disease is unknown. We hypothesized that greater RV mass and RV end-diastolic volume (RVEDV), smaller RV stroke volume (RVSV), and lower RV ejection fraction (RVEF) measured by cardiac magnetic resonance imaging (MRI) in participants free of clinical cardiovascular disease at baseline would be associated with a greater risk of self-reported dyspnea.

Methods

The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac MRIs on participants without clinical cardiovascular disease between 2000 and 2002. We excluded subjects who reported “prevalent” dyspnea at the first assessment (24 months). The presence of dyspnea was assessed at 24 months, 42 months, and 60 months from baseline. Cox proportional hazards models were used to examine the relationship between RV measures and incident dyspnea.

Results

In the final study sample (N = 2763), there were significant interactions between RV measures and sex in terms of the risk of dyspnea (p<0.05). Among men (N = 1453), lower RV mass (p = 0.003), smaller RVEDV (p<0.001), smaller RV end-systolic volume (RVESV) (p = 0.03) and decreased RVSV (p<0.001) were associated with an increased risk of developing dyspnea after adjusting for covariates. Associations remained after adjusting for left ventricular function and lung function. However, there were no significant associations between RV measures and the risk of dyspnea in women.

Conclusions

Lower RV mass and smaller RV volumes were associated with an increased risk of dyspnea in men, but not in women.     

Matrix metalloproteinase-9 and plasminogen activator inhibitor-1 are associated with right ventricular structure and function: The MESA-RV Study

Elevated resistance and reduced compliance of the pulmonary vasculature increase right ventricular (RV) afterload. Local and systemic inflammation and haemostatic abnormalities are prominent in pulmonary vascular diseases. We hypothesized that plasma biomarker levels indicating greater inflammation and coagulability associated with pulmonary vascular disease would be associated with RV structure and function measured by cardiac magnetic resonance imaging (MRI). The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac MRI among participants aged 45–84 years without clinical cardiovascular disease. We assessed the associations of RV mass, RV end-diastolic volume (RVEDV), RV stroke volume (RVSV) and RV ejection fraction (RVEF) with plasma measures of inflammation (matrix metalloproteinase (MMP)-3 and -9, intercellular adhesion molecule (ICAM)-1, tumour necrosis factor receptor (TNF-R1), and E-selectin) and thrombosis (plasminogen activator inhibitor (PAI)-1, tissue factor, tissue factor pathway inhibitor and CD40 ligand).The study sample included 731 subjects. Higher MMP-9 levels were associated with lower RV mass before and after adjustment for left ventricular (LV) mass (p?=?0.008 and p?=?0.044, respectively). Higher levels of MMP-9 and PAI-1 were also associated with smaller RVEDV (p<0.05). Higher PAI-1 levels were associated with lower RVEF even after adjustment for LV ejection fraction (p?=?0.017). In conclusion, MMP-9 and PAI-1 are associated with changes in RV structure and function which could be potentially related to a subclinical increase in pulmonary vascular resistance.     

Real-Time Three-Dimensional Echocardiography to Assess Right Ventricle Function in Patients with Pulmonary Hypertension

Background

The convenience and availability of real-time three-dimensional echocardiography (RT3DE) makes it an attractive candidate for assessing right ventricle function. However, the viability of RT3DE is not conclusive.

Aim of Study

This study aims to evaluate RT3DE relative to cardiac magnetic resonance and 2-dimensional echocardiography (2DE) for measuring right ventricular systolic function in patients with pulmonary hypertension.

Methods

Patients with pulmonary hypertension (n = 23) underwent cardiac magnetic resonance, 2DE, and RT3DE. Specifically, 2DE was used to measure the right ventricular index of myocardial performance (RIMP), fractional area change, tricuspid annular plane systolic excursion (TAPSE), and tissue Doppler-derived tricuspid annular systolic velocity (S′). Cardiac magnetic resonance and RT3DE were used to measure right ventricular end-diastolic volume (RVEDV) and end-systolic volume (RVESV). The right ventricular ejection fraction (RVEF) was calculated.

Results

Regarding the measurements taken by 2DE, RVEF positively correlated with fractional area change (r = 0.595, P = 0.003) and S′(r = 0.489, P = 0.018), and negatively correlated with RIMP (r = −0.745, P = 0.000). There was no association between RVEF and TAPSE (r = −0.029, P = 0.896). There existed a close correlation between the values of RVEDV, RVESV, and RVEF as measured by RT3DE and CMR respectively (P<0.001); Bland-Altmanan analyses showed good agreement between them.

Conclusion

RT3DE was a viable method for noninvasive, accurate assessment of right ventricular systolic function in patients with pulmonary hypertension.     

Continuous monitoring of right ventricular volume changes using a conductance catheter in the rabbit.

To assess the reliability of conductance (G) catheter for evaluating right ventricular (RV) volume changes, a miniature (3.5F) six-electrode catheter was developed and tested in 11 New Zealand rabbit hearts. In five animals the heart was excised; in six it was left in the thorax. RV conductance was recorded while the RV was filled with blood in 0.25-ml steps at different left ventricular (LV) volumes. Linear correlation of measured conductance vs. reference volumes was computed. RV conductance was highly correlated with reference volume [correlation coefficient (r) ranging from 0.991 to 0.999]. Slope of regression lines was not significantly affected by LV volume variations in 1-ml steps or by acute conductance changes of structures surrounding the heart, whereas the intercept was affected only by the 0- to 1-ml LV volume change. In four rabbits, RV conductance changes during a cardiac cycle [stroke volume- (SV) G] were compared in vivo with electromagnetic flow probe-derived estimates of SV (SVem) as stroke volume was varied by graded inferior vena caval occlusion. SV-G correlated well with SVem (r ranging from 0.92 to 0.96). This correlation persisted after the thorax was filled with saline; however, significant differences were found in individual slopes (P < 0.001). These results show that the conductance catheter has a potential to reliably monitor in vivo relative RV volume changes in small-animal hearts.     

Ventilatory and perceptual responses to cycle exercise in obese women.

The main purpose of this study was to examine the relative contribution of respiratory mechanical factors and the increased metabolic cost of locomotion to exertional breathlessness in obese women. We examined the relationship of intensity of breathlessness to ventilation (VE) when exertional oxygen uptake (VO2) of obesity was minimized by cycle exercise. Eighteen middle-aged (54+/-8 yr, mean+/-SD) obese [body mass index (BMI) 40.2+/-7.8 kg/m2] and 13 age-matched normal-weight (BMI 23.3+/-1.7 kg/m2) women were studied. Breathlessness at higher submaximal cycle work rates was significantly increased (by>or=1 Borg unit) in obese compared with normal-weight women, in association with a 35-45% increase in Ve and a higher metabolic cost of exercise. Obese women demonstrated greater resting expiratory flow limitation, reduced resting end-expiratory lung volume (EELV)(by 20%), and progressive increases in dynamic EELV during exercise: peak inspiratory capacity (IC) decreased by 16% (0.39 liter) of the resting value. VE/VO2 slopes were unchanged in obesity. Breathlessness ratings at any given VE or VO2 were not increased in obesity, suggesting that respiratory mechanical factors were not contributory. Our results indicate that in obese women, recruitment of resting IC and dynamic increases in EELV with exercise served to optimize operating lung volumes and to attenuate expiratory flow limitation so as to accommodate the increased ventilatory demand without increased breathlessness.     

Myocardial function defined by strain rate and strain during alterations in inotropic states and heart rate

For porcine myocardium, ultrasonic regional deformation parameters, systolic strain (epsilon(sys)) and peak systolic strain rate (SR(sys)), were compared with stroke volume (SV) and contractility [contractility index (CI)] measured as the ratio of end-systolic strain to end-systolic wall stress. Heart rate (HR) and contractility were varied by atrial pacing (AP = 120-180 beats/min, n = 7), incremental dobutamine infusion (DI = 2.5-20 microg. kg(-1). min(-1), n = 7), or continuous esmolol infusion (0.5 mg. kg(-1). min(-1)) + subsequent pacing (120-180 beats/min) (EI group, n = 6). Baseline SR(sys) and epsilon(sys) averaged 5.0 +/- 0.4 s(-1) and 60 +/- 4%. SR(sys) and CI increased linearly with DI (20 microg. kg(-1). min(-1); SR(sys) = 9.9 +/- 0.7 s(-1), P < 0.0001) and decreased with EI (SR(sys) = 3.4 +/- 0.1 s(-1), P < 0.01). During pacing, SR(sys) and CI remained unchanged in the AP and EI groups. During DI, epsilon(sys) and SV initially increased (5 microg. kg(-1). min(-1); epsilon(sys) = 77 +/- 6%, P < 0.01) and then progressively returned to baseline. During EI, SV and epsilon(sys) decreased (epsilon(sys) = 38 +/- 2%, P < 0.001). Pacing also decreased SV and epsilon(sys) in the AP (180 beats/min; epsilon(sys) = 36 +/- 2%, P < 0.001) and EI groups (180 beats/min; epsilon(sys) = 25 +/- 3%, P < 0.001). Thus, for normal myocardium, SR(sys) reflects regional contractile function (being relatively independent of HR), whereas epsilon(sys) reflects changes in SV.     

Proposed tests for measuring the running velocity at the oxygen consumption and heart rate thresholds for treadmill exercise

The purposes of this study were to (a) determine if the mathematical model used to estimate the physical working capacity at the oxygen consumption threshold (PWC(VO(2))) and physical working capacity at the heart rate threshold (PWC(HRT)) for cycle ergometry could be applied to treadmill running; (b) propose new fatigue thresholds called the running velocity at the oxygen uptake threshold (RV(VO(2))) and running velocity at the heart rate threshold (RV(HRT)) for treadmill exercise; and (c) statistically compare the velocities at the RV(VO(2)), RV(HRT), and ventilatory threshold (VT). Seven aerobically trained adult volunteers (mean +/- SD: age 24.0 +/- 3.9 years, Vo(2) max 56.7 +/- 7.1 ml.kg(-1).min(-1)) performed a maximal treadmill test to determine Vo(2) peak and VT as well as four 8-minute submaximal workbouts for the determination of RV(VO(2)) and RV(HRT). One-way repeated-measures analysis of variance indicated that there were no significant (p > 0.05) mean differences among the running velocities for the RV(VO(2)), RV(HRT), and VT. The results of this study indicated that the mathematical model used to estimate PWC(VO(2)) and PWC(HRT) for cycle ergometry could be applied to treadmill running. Furthermore, the RV(VO(2)) and RV(HRT) test may provide submaximal techniques for estimating the VT.     

Real-Time 3-Dimensional Echocardiographic Assessment of Ventricular Volume,Mass, and Function in Human Fetuses

Objectives

We sought to determine the feasibility and reproducibility of real-time 3-dimensional echocardiography (RT3DE) for evaluation of cardiac volume, mass, and function and to characterize maturational changes of these measurements in human fetuses.

Methods

Eighty pregnant women in the 2^nd and 3^rd trimesters (59 with normal fetuses and 21 with fetuses with congenital heart disease [CHD]) were enrolled. We acquired RT3DE images using a matrix-array transducer. RT3DE measurements of volume, mass, stroke volume (SV), combined cardiac output (CCO), and ejection fraction (EF) were obtained. Images were scored and analyzed by two blinded independent observers. Inter- and intraobserver variabilities and correlations between fetal cardiac indices and gestational age were determined.

Results

Fifty-two of 59 normal data sets (88%) and 9 of 21 CHD data sets (43%) were feasible for analysis. In normal fetuses, the right ventricle (RV) is larger than the left ventricle (LV) (P<0.05), but no difference exists between the LV and RV in mass, SV, CO, and CO/CCO. The EFs for the LV and RV were diminished; the RVSV/LVSV was reduced in CHD fetuses compared with normal fetuses (P<0.05). Fetal ventricular volumes, mass, SV, and CCO fit best into exponential curves with gestational age, but LVEF, RVEF, and RVSV/LVSV remain relatively constant.

Conclusions

RT3DE is feasible and reproducible for assessment of LV and RV volume, mass, and function, especially in normal fetuses. Gestational growth of these measures, except for EF, is exponential in normal and CHD fetuses. CHD fetuses exhibit diminished LV and RV EFs.     

Selective serotonin reuptake inhibitor use is associated with right ventricular structure and function: the MESA-right ventricle study

Purpose

Serotonin and the serotonin transporter have been implicated in the development of pulmonary hypertension (PH). Selective serotonin reuptake inhibitors (SSRIs) may have a role in PH treatment, but the effects of SSRI use on right ventricular (RV) structure and function are unknown. We hypothesized that SSRI use would be associated with RV morphology in a large cohort without cardiovascular disease (N = 4114).

Methods

SSRI use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were assessed via cardiac magnetic resonance imaging. The cross-sectional relationship between SSRI use and each RV measure was assessed using multivariable linear regression; analyses for RV mass and end-diastolic volume (RVEDV) were stratified by sex.

Results

After adjustment for multiple covariates including depression and left ventricular measures, SSRI use was associated with larger RV stroke volume (RVSV) (2.75 mL, 95% confidence interval [CI] 0.48–5.02 mL, p = 0.02). Among men only, SSRI use was associated with greater RV mass (1.08 g, 95% CI 0.19–1.97 g, p = 0.02) and larger RVEDV (7.71 mL, 95% 3.02–12.40 mL, p = 0.001). SSRI use may have been associated with larger RVEDV among women and larger RV end-systolic volume in both sexes.

Conclusions

SSRI use was associated with higher RVSV in cardiovascular disease-free individuals and, among men, greater RV mass and larger RVEDV. The effects of SSRI use in patients with (or at risk for) RV dysfunction and the role of sex in modifying this relationship warrant further study.     

Cardiac output and muscle blood flow during rest-associated apneas of elephant seals

In order to evaluate hemodynamics and blood flow during rest-associated apnea in young elephant seals (Mirounga angustirostris), cardiac outputs (CO, thermodilution), heart rates (HR), and muscle blood flow (MBF, laser Doppler flowmetry) were measured. Mean apneic COs and HRs of three seals were 46% and 39% less than eupneic values, respectively (2.1+/-0.3 vs. 4.0+/-0.1 mL kg(-1) s(-1), and 54+/-6 vs. 89+/-14 beats min(-1)). The mean apneic stroke volume (SV) was not significantly different from the eupneic value (2.3+/-0.2 vs. 2.7+/-0.5 mL kg(-1)). Mean apneic MBF of three seals was 51% of the eupneic value. The decline in MBF during apnea was gradual, and variable in both rate and magnitude. In contrast to values previously documented in seals during forced submersions (FS), CO and SV during rest-associated apneas were maintained at levels characteristic of previously published values in similarly-sized terrestrial mammals at rest. Apneic COs of such magnitude and incomplete muscle ischemia during the apnea suggest that (1) most organs are not ischemic during rest-associated apneas, (2) the blood O(2) depletion rate is greater during rest-associated apneas than during FS, and (3) the blood O(2) store is not completely isolated from muscle during rest-associated apneas.     

Mild obesity does not limit change in end-expiratory lung volume during cycling in young women.

To investigate the effects of obesity on the regulation of end-expiratory lung volume (EELV) during exercise we studied nine obese (41 +/- 6% body fat and 35 +/- 7 yr, mean +/- SD) and eight lean (18 +/- 3% body fat and 34 +/- 4 yr) women. We hypothesized that the simple mass loading of obesity would constrain the decrease in EELV in the supine position and during exercise. All subjects underwent respiratory mechanics measurements in the supine and seated positions, and during graded cycle ergometry to exhaustion. Data were analyzed between groups by independent t-test in the supine and seated postures, and during exercise at ventilatory threshold and peak. Total lung capacity (TLC) was reduced in the obese women (P < 0.05). EELV was significantly lower in the obese subjects in the supine (37 +/- 6 vs. 45 +/- 5% TLC) and seated (45 +/- 6 vs. 53 +/- 5% TLC) positions and at ventilatory threshold (41 +/- 4 vs. 49 +/- 5% TLC) (P < 0.01). In conclusion, despite reduced resting lung volumes and alterations in respiratory mechanics during exercise, mild obesity in women does not appear to constrain EELV during cycling nor does it limit exercise capacity. Also, these data suggest that other nonmechanical factors also regulate the level of EELV during exercise.     

Liver Lobe Volumes and the Ratios of Liver Lobe Volumes to Spleen Volume on Magnetic Resonance Imaging for Staging Liver Fibrosis in a Minipig Model

Objective

To investigate liver lobe volumes and the ratios of liver lobe volumes to spleen volume measured with magnetic resonance imaging (MRI) for quantitatively monitoring and staging liver fibrosis.

Methods

Animal study was approved by Institutional Animal Care and Use Committee. Sixteen minipigs were prospectively used to model liver fibrosis, and underwent abdominal gadolinium-enhanced MRI on 0, 5^th, 9^th, 16^th and 21^st weekend after modeling this disease staged by biopsy according to METAVIR classification system. On MRI, volume parameters including left lateral liver lobe volume (LLV), left medial liver lobe volume (LMV), right liver lobe volume (RV), caudate lobe volume (CV), and spleen volume (SV) were measured; and LLV/SV, LMV/SV, RV/SV and CV/SV were calculated. Statistical analyses were performed for staging this fibrosis.

Results

LLV and CV increased with increasing stage of fibrosis (r = 0.711, 0.526, respectively; all P < 0.05). RV and LMV increased from stage 0 to 2 and decreased from 2 to 4; and RV/SV decreased from 0 to 1, increased from 1 to 2, and decreased from 3 to 4 (all P > 0.05). LLV/SV, LMV/SV and CV/SV decreased from stage 0 to 4 (r = -0.566, -0.748 and -0.620, respectively; all P < 0.05). LLV, CV, LLV/SV, LMV/SV, RV/SV, and CV/SV could distinguish stage 0–1 from 2–4 and 0–2 from 3–4 (all P < 0.05). Among these parameters, LLV and LMV/SV could best classify stage ≥2 and ≥3, respectively (area under receiver operating characteristic curve = 0.893 and 0.946, respectively).

Conclusion

LLV and LMV/SV complement each other in staging liver fibrosis, and both parameters should be used to stage this disease.     

The quantitative relationship between longitudinal and radial function in left, right, and total heart pumping in humans

The total heart volume variation (THVV) during systole has been proposed to be caused by radial function of the ventricles, but definitive data for both ventricles have not been presented. Furthermore, the right ventricle (RV) has been suggested to have a greater longitudinal pumping component than the left ventricle (LV). Therefore, we aimed to compare the stroke volume (SV) generated by radial function to the volume variation of the left, right, and total heart. To do this, we also needed to develop a new method for measuring the contribution of the longitudinal atrioventricular plane displacement (AVPD) to the RVSV (RVSV(AVPD)). For our study, 11 volunteers underwent cine MRI in the short- and long-axis planes and MRI flow measurement in all vessels leading to and from the heart. The left, right, and total heart showed correlations between volume variation from flow measurements and radial function calculated as SV minus the longitudinal function (r = 0.81, P < 0.01; r = 0.80, P < 0.01; and r = 0.92, P < 0.001, respectively). Compared with the LV, the RV had a greater AVPD (23.4 +/- 0.8 vs. 16.4 +/- 0.5 mm), center of volume movement (13.0 +/- 0.7 vs. 7.8 +/- 0.4 mm), and, RVSV(AVPD) (82 +/- 2% vs. 60 +/- 2%) (P < 0.001 for all). We found that THVV is predominantly caused by radial function of the ventricles. Longitudinal AVPD accounts for approximately 80% of the RVSV, compared with approximately 60% for the LVSV. This difference explains the larger portion of THVV found on the left side of the heart.     

Volume displaced by diaphragm motion in emphysema.

To examine the effect of hyperinflation on the volume displaced by diaphragm motion (DeltaVdi), we compared nine subjects with emphysema and severe hyperinflation [residual volume (RV)/total lung capacity (TLC) 0.65 +/- 0.08; mean +/- SD] with 10 healthy controls. Posteroanterior and lateral chest X rays at RV, functional residual capacity, one-half inspiratory capacity, and TLC were used to measure the length of diaphragm apposed to ribcage (Lap), cross-sectional area of the pulmonary ribcage, DeltaVdi, and volume beneath the lung-apposed dome of the diaphragm. Emphysema subjects, relative to controls, had increased Lap at comparable lung volumes (4.3 vs. 1.0 cm near predicted TLC, 95% confidence interval 3.4-5.2 vs. 0-2.1), pulmonary rib cage cross-sectional area (emphysema/controls 1.22 +/- 0.03, P < 0.001 at functional residual capacity), and DeltaVdi/DeltaLap (0.25 vs. 0.14 liters/cm, P < 0.05). During a vital capacity inspiration, relative to controls, DeltaVdi was normal in five (1.94 +/- 0.51 liters) and decreased in four (0.51 +/- 0.40 liters) emphysema subjects, and volume beneath the dome did not increase in emphysema (0 +/- 0.36 vs. 0.82 +/- 0.80 liters, P < 0.05). We conclude that DeltaVdi can be normal in emphysema because 1) hyperinflation is shared between ribcage and diaphragm, preserving Lap, and 2) the diaphragm remains flat during inspiration.     

Cardiac atrophy in women following bed rest.

Both chronic microgravity exposure and long-duration bed rest induce cardiac atrophy, which leads to reduced standing stroke volume and orthostatic intolerance. However, despite the fact that women appear to be more susceptible to postspaceflight presyncope and orthostatic hypotension than male astronauts, most previous high-resolution studies of cardiac morphology following microgravity have been performed only in men. Because female athletes have less physiological hypertrophy than male athletes, we reasoned that they also might have altered physiological cardiac atrophy after bed rest. Magnetic resonance imaging was performed in 24 healthy young women (32.1 +/- 4 yr) to measure left ventricular (LV) and right ventricular (RV) mass, volumes, and morphology accurately before and after 60 days of 6 degrees head-down tilt (HDT) bed rest. Subjects were matched and then randomly assigned to sedentary bed rest (controls, n = 8) or two treatment groups consisting of 1) exercise training using supine treadmill running within lower body negative pressure plus resistive training (n = 8), or 2) protein (0.45 g x kg(-1) x day(-1) increase) plus branched-chain amino acid (BCAA) (7.2 g/day) supplementation (n = 8). After sedentary bed rest without nutritional supplementation, there were significant reductions in LV (96 +/- 26 to 77 +/- 25 ml; P = 0.03) and RV volumes (104 +/- 33 to 86 +/- 25 ml; P = 0.02), LV (2.2 +/- 0.2 to 2.0 +/- 0.2 g/kg; P = 0.003) and RV masses (0.8 +/- 0.1 to 0.6 +/- 0.1 g/kg; P < 0.001), and the length of the major axis of the LV (90 +/- 6 to 84 +/- 7 mm. P < 0.001), similar to what has been observed previously in men (8.0%; Perhonen MA, Franco F, Lane LD, Buckey JC, Blomqvist Zerwekh JE, Peshock RM, Weatherall PT, Levine BD. J Appl Physiol 91: 645-653, 2001). In contrast, there were no significant reductions in LV or RV volumes in the exercise-trained group, and the length of the major axis was preserved. Moreover, there were significant increases in LV (1.9 +/- 0.4 to 2.3 +/- 0.3 g/kg; P < 0.001) and RV masses (0.7 +/- 0.1 to 0.8 +/- 0.2 g/kg; P = 0.002), as well as mean wall thickness (9 +/- 2 to 11 +/- 1 mm; P = 0.02). The interaction between sedentary and exercise LV and RV masses was highly significant (P < 0.0001). Protein and BCAA supplementation led to an intermediate phenotype with no change in LV or RV mass after bed rest, but there remained a significant reduction in LV volume (103 +/- 14 to 80 +/- 16 ml; P = 0.02) and major-axis length (91 +/- 5 to 88 +/- 7 mm; P = 0.003). All subjects lost an equivalent amount of body mass (3.4 +/- 0.2 kg control; 3.1 +/- 0.04 kg exercise; 2.8 +/- 0.1 kg protein). Cardiac atrophy occurs in women similar to men following sedentary 60 days HDT bed rest. However, exercise training and, to a lesser extent, protein supplementation may be potential countermeasures to the cardiac atrophy associated with chronic unloading conditions such as in spaceflight and prolonged bed rest.     

Airway obstruction during periodic breathing in premature infants

To characterize changes in pulmonary resistance, timing, and respiratory drive during periodic breathing, we studied 10 healthy preterm infants (body wt 1,340 +/- 240 g, postconceptional age 35 +/- 2 wk). Periodic breathing in these infants was defined by characteristic cycles of ventilation with intervening respiratory pauses greater than or equal to 2 s. Nasal airflow was recorded with a pneumotachometer, and esophageal or pharyngeal pressure was recorded with a fluid-filled catheter. Pulmonary resistance at half-maximal tidal volume, inspiratory time (TI), expiratory time (TE), and mean inspiratory flow (VT/TI) were derived from computer analysis of five cycles of periodic breathing per infant. In 80% of infants periodic breathing was accompanied by completely obstructed breaths at the onset of ventilatory cycles; the site of airway obstruction occurred within the pharynx. The first one-third of the ventilatory phase of each cycle was accompanied by the highest airway resistance of the entire cycle (168 +/- 98 cmH2O.l-1.s). In all infants TI was greatest at the onset of the ventilatory cycle, VT/TI was maximal at the midpoint of the cycle, and TE was longest in the latter two-thirds of each cycle. A characteristic increase and subsequent decrease of 4.5 +/- 1.9 ml in end-expiratory volume also occurred within each cycle. These results demonstrate that partial or complete airway obstruction occurs during periodic breathing. Both apnea and periodic breathing share the element of upper airway instability common to premature infants.     

Pharyngeal cross-sectional area in normal men and women

Pharyngeal size and the dynamic behavior of the upper airway may be important factors in modulating respiratory airflow. Patients with obstructive sleep apnea are known to have reduced pharyngeal cross-sectional area. However, no systematic measurements of pharyngeal area in healthy asymptomatic subjects are available, in part due to the lack of simple, rapid, and noninvasive measurement techniques. We utilized the acoustic reflection technique to measure pharyngeal cross-sectional area in 24 healthy volunteers (14 males, 10 females). Pharyngeal area was measured during a continuous slow expiration from total lung capacity (TLC) to residual volume (RV). We compared pharyngeal cross-sectional areas in males and females at three lung volumes: TLC, 50% of vital capacity (VC), and RV. In males, pharyngeal areas (means +/- SD) were 6.4 +/- 1.3 cm2 at TLC, 5.4 +/- 0.9 cm2 at 50% VC, and 4.1 +/- 0.8 cm2 at RV. In females, pharyngeal areas were 4.8 +/- 0.6 cm2 at TLC, 4.2 +/- 0.5 cm2 at 50% VC, and 3.7 +/- 0.6 cm2 at RV. The difference in area between males and females was statistically significant at TLC and 50% VC but not at RV. However, when the pharyngeal cross-sectional area was normalized for body surface area, this difference was not significant. In males there was a negative correlation of pharyngeal area with age. We conclude that sex differences in pharyngeal area are related to body size, pharyngeal area shows a similar variation with lung volumes in males and females, and in males pharyngeal area reduces with age.     

Hemodynamic effects of synchronous high-frequency jet ventilation during acute hypovolemia

We studied the effects of synchronous cardiac cycle-specific high-frequency jet ventilation (HFJV) in pentobarbital-anesthetized, splenectomized, closed-chest dogs to test the hypothesis that phasic inspiratory increases in intrathoracic pressure (ITP) selectively timed to specific periods of the cardiac cycle have different hemodynamic effects during both hypovolemia (acute hemorrhage, 20 ml/kg) and neurogenic vasomotor shock (hexamethonium, 10 mg/kg) than those observed during normovolemic control conditions. Ventricular stroke volumes (SV) were measured by electromagnetic flow probes. The influence of changes in venous return (VR) on the subsequent hemodynamic response to synchronous HFJV was analyzed using instantaneous VR curves (M. R. Pinsky, J. Appl. Physiol. 56:765-771, 1984). During hemorrhage the VR curve was shifted leftward with concomitant reductions in apneic SV (15.4 +/- 3.8 to 11.2 +/- 3.6 ml, mean +/- SD), (P less than 0.01) that were accentuated by HFJV (P less than 0.01), except when the phasic inspiratory increases in ITP during HFJV were timed to occur during late diastole (-4% apneic SV, NS). SV was greater with late diastolic pulses than with other timed synchronous ITP pulses during hypovolemia (P less than 0.01). During ganglionic blockade, arterial pressure decreased (139 +/- 14 to 76 +/- 18 Torr, P less than 0.001), but VR was preserved at control levels, and no significant cardiac cycle-specific HFJV effects occurred. We conclude that SV reductions associated with positive-pressure ventilation during acute hypovolemia are minimized by HFJV synchronized to late diastole but that this effect is preload dependent.