Naomi C. Chesler

Exercise stress echocardiography for the study of the pulmonary circulation.

Exercise stress tests have been used for the diagnosis of pulmonary hypertension, but with variable protocols and uncertain limits of normal. The pulmonary haemodynamic response to progressively increased workload and recovery was investigated by Doppler echocardiography in 25 healthy volunteers aged 19–62 yrs (mean 36 yrs). Mean pulmonary artery pressure (P̄pa) was estimated from the maximum velocity of tricuspid regurgitation. Cardiac output (Q) was calculated from the aortic velocity-time integral. Slopes and extrapolated pressure intercepts of P̄pa–Q plots were calculated after using the adjustment of Poon for individual variability. A pulmonary vascular distensibility α was calculated from each P̄pa–Q plot to estimate compliance. P̄pa increased from 14±3 mmHg to 30±7 mmHg, and decreased to 19±4 mmHg after 5 min recovery. The slope of P̄pa–Q was 1.37±0.65 mmHg·min−1·L−1 with an extrapolated pressure intercept of 8.2±3.6 mmHg and an α of 0.017±0.018 mmHg−1. These results agree with those of previous invasive studies. Multipoint P̄pa–Q plots were well described by a linear approximation, from which resistance can be calulated. We conclude that exercise echocardiography of the pulmonary circulation is feasible and provides realistic resistance and compliance estimations. Measurements during recovery are unreliable because of rapid return to baseline.

Transmural pressure induces matrix-degrading activity in porcine arteries ex vivo

Extracellular matrix components must be degraded and resynthesized for vascular remodeling to occur. We hypothesized that the hemodynamic environment regulates activity of matrix metalloproteinases (MMPs), the primary agents for in vivo matrix degradation, during vascular remodeling in response to changes in transmural pressure and shear stress. Pathological hemodynamic conditions were reproduced in an ex vivo system in which we maintained porcine carotid arteries for 24 and 48 h. Total levels of MMP-2 and MMP-9 extracted from tissue homogenates and analyzed by SDS-PAGE zymography were stimulated by transmural pressure and were unaffected by shear stress changes. Degradation of two specific gelatinase substrates, gelatin and elastin, increased with increasing pressure, but the degradation was not affected by shear stress changes in tissue specimens analyzed using in situ zymography (gelatin) and fluorescent measurement of endogenous elastin degradation (elastin). Our results suggest that transmural pressure activates at least two members of the MMP family and that activity of these enzymes is accompanied by degradation of matrix components, effects that may be implicated in hypertensive vascular remodeling.

Pulmonary Vascular Wall Stiffness: An Important Contributor to the Increased Right Ventricular Afterload with Pulmonary Hypertension:

Pulmonary hypertension (PH) is associated with structural and mechanical changes in the pulmonary vascular bed that increase right ventricular (RV) afterload. These changes, characterized by narrowing and stiffening, occur in both proximal and distal pulmonary arteries (PAs). An important consequence of arterial narrowing is increased pulmonary vascular resistance (PVR). Arterial stiffening, which can occur in both the proximal and distal pulmonary arteries, is an important index of disease progression and is a significant contributor to increased RV afterload in PH. In particular, arterial narrowing and stiffening increase the RV afterload by increasing steady and oscillatory RV work, respectively. Here we review the current state of knowledge of the causes and consequences of pulmonary arterial stiffening in PH and its impact on RV function. We review direct and indirect techniques for measuring proximal and distal pulmonary arterial stiffness, measures of arterial stiffness including elastic modulus, incremental elastic modulus, stiffness coefficient β and others, the changes in cellular function and the extracellular matrix proteins that contribute to pulmonary arterial stiffening, the consequences of PA stiffening for RV function and the clinical implications of pulmonary vascular stiffening for PH progression. Future investigation of the relationship between PA stiffening and RV dysfunction may facilitate new therapies aimed at improving RV function and thus ultimately reducing mortality in PH.

Exercise Stress Echocardiography of the Pulmonary Circulation: Limits of Normal and Sex Differences

BACKGROUND Exercise stress echocardiography has not been recommended in the diagnostic workup of pulmonary hypertension because of insufficient certainty about feasibility and limits of normal. METHODS Doppler echocardiography pulmonary hemodynamic measurements were performed at a progressively increased workload in 56 healthy male and 57 healthy female volunteers aged 19 to 63 years. Mean pulmonary artery pressure (mPAP) was estimated from the maximal tricuspid regurgitation jet velocity. Cardiac index was calculated from the left ventricular outflow velocity-time integral. Pulmonary vascular distensibility a index, the percentage change of vessel diameter permm Hg of mPAP, was calculated from multipoint mPAP-cardiac output (CO) plots. RESULTS Peak exercise at 175 ±50 W was associated with an mPAP of 33±7 mm Hg and a CO of 18 ±5 L/min. The slope of mPAP-CO relationships was 1.5 ± 0.5 mm Hg/L/min, and the distensibility coefficient ( α ) was 1.3%± 1.0%/mm Hg. Maximal workload and cardiac index were higher in men than in women ( P , .05), but mPAP-cardiac index relationships were not different. However,women had a higher a (1.6%± 1.3%/mm Hg vs 1.1%± 0.6%/mm Hg, P < .05). The average mPAP-cardiac index slope was higher and a lower in subjects ≥50 years old. Upper limits of normal of mPAP at exercise were 34 mm Hg at a CO , 10 L/min, 45 mm Hg at a CO <20 L/min, and 52 mm Hg at a CO<30 L/min. These values are in keeping with previously reported invasive measurements. CONCLUSIONS Exercise stress echocardiography of the pulmonary circulation is feasible and allows for fl ow-corrected definition of upper limits of normal. Women have a more distensible pulmonary circulation.

Original ResearchPulmonary Vascular DiseaseExercise Stress Echocardiography of the Pulmonary Circulation: Limits of Normal and Sex Differences

BACKGROUND Exercise stress echocardiography has not been recommended in the diagnostic workup of pulmonary hypertension because of insufficient certainty about feasibility and limits of normal. METHODS Doppler echocardiography pulmonary hemodynamic measurements were performed at a progressively increased workload in 56 healthy male and 57 healthy female volunteers aged 19 to 63 years. Mean pulmonary artery pressure (mPAP) was estimated from the maximal tricuspid regurgitation jet velocity. Cardiac index was calculated from the left ventricular outflow velocity-time integral. Pulmonary vascular distensibility a index, the percentage change of vessel diameter permm Hg of mPAP, was calculated from multipoint mPAP-cardiac output (CO) plots. RESULTS Peak exercise at 175 ±50 W was associated with an mPAP of 33±7 mm Hg and a CO of 18 ±5 L/min. The slope of mPAP-CO relationships was 1.5 ± 0.5 mm Hg/L/min, and the distensibility coefficient ( α ) was 1.3%± 1.0%/mm Hg. Maximal workload and cardiac index were higher in men than in women ( P , .05), but mPAP-cardiac index relationships were not different. However,women had a higher a (1.6%± 1.3%/mm Hg vs 1.1%± 0.6%/mm Hg, P < .05). The average mPAP-cardiac index slope was higher and a lower in subjects ≥50 years old. Upper limits of normal of mPAP at exercise were 34 mm Hg at a CO , 10 L/min, 45 mm Hg at a CO <20 L/min, and 52 mm Hg at a CO<30 L/min. These values are in keeping with previously reported invasive measurements. CONCLUSIONS Exercise stress echocardiography of the pulmonary circulation is feasible and allows for fl ow-corrected definition of upper limits of normal. Women have a more distensible pulmonary circulation.

Surface EMG as a Fatigue Indicator During FES-induced Isometric Muscle Contractions

The electromyogram (EMG) signal has potential as an indicator of stimulated muscle fatigue in applications of functional electrical stimulation (FES). In particular, it could be used to detect near lower limb collapse due to the associated muscle fatigue in FES-aided standing systems and thereby prevent falling. Surface EMG measurement, however, is hampered by stimulation artifact during FES. Modified surface stimulation and EMG detection equipment were designed and built to minimize this artifact and to permit detection of the electrical signal generated by the muscle during contraction. Artifact reduction techniques included shorting stimulator output leads between stimulus pulses and limiting and blanking slew rate in the EMG processing stage. Isometric fatigue experiments were performed by stimulating the quadriceps muscle of 20 able-bodied (a total of 125 trials) and three spinal cord injured (18 trials) subjects. Fatigue-tracking performance indicators were derived from the root-mean-square (RMS) of the EMG amplitude and from the median frequency (MF) of the EMG power spectral content. The results demonstrate that reliable fatigue tracking indicators for practical FES applications will be difficult to obtain, but that amplitude-based measures in spinal cord injured subjects show promise.

The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension

Hypoxic pulmonary hypertension (HPH) causes extralobar pulmonary artery (PA) stiffening, which potentially impairs right ventricular systolic function. Changes in the extracellular matrix proteins collagen and elastin have been suggested to contribute to this arterial stiffening. We hypothesized that vascular collagen accumulation is a major cause of extralobar PA stiffening in HPH and tested our hypothesis with transgenic mice that synthesize collagen type I resistant to collagenase degradation (Col1a1(R/R)). These mice and littermate controls that have normal collagen degradation (Col1a1(+/+)) were exposed to hypoxia for 10 days; some were allowed to recover for 32 days. In vivo PA pressure and isolated PA mechanical properties and collagen and elastin content were measured for all groups. Vasoactive studies were also performed with U-46619, Y-27632, or calcium- and magnesium-free medium. Pulmonary hypertension occurred in both mouse strains due to chronic hypoxia and resolved with recovery. HPH caused significant PA mechanical changes in both mouse strains: circumferential stretch decreased, and mid-to-high-strain circumferential elastic modulus increased (P < 0.05 for both). Impaired collagen type I degradation prevented a return to baseline mechanical properties with recovery and, in fact, led to an increase in the low and mid-to-high-strain moduli compared with hypoxia (P < 0.05 for both). Significant changes in collagen content were found, which tended to follow changes in mid-to-high-strain elastic modulus. No significant changes in elastin content or vasoactivity were observed. Our results demonstrate that collagen content is important to extralobar PA stiffening caused by chronic hypoxia.

Early Effects of Arterial Hemodynamic Conditions on Human Saphenous Veins Perfused Ex Vivo

Exposure to the arterial hemodynamic environment is thought to be a potential trigger for the pathological remodeling of saphenous vein grafts. Using matched pairs of freshly isolated human saphenous vein, we analyzed the early effects of ex vivo hemodynamic conditions mimicking the venous (native) compared with arterial (graft) environment on the key components of vascular remodeling, ie, matrix metalloproteinase (MMP)-9 and MMP-2 and cell proliferation. Interestingly, we found that arterial conditions halved latent MMP-9 (50+/-11%, P=0.01) and MMP-2 (44+/-6%, P=0.005) levels relative to matched vein pairs maintained ex vivo under venous perfusion for up to 3 days. Immunostaining supported decreased MMP levels in the innermost area of arterially perfused veins. Either decreased synthesis or increased posttranslational processing may decrease MMP zymogen levels. Biosynthetic radiolabeling showed that arterial perfusion actually increased MMP-9 and MMP-2 production. When we then examined potential pathways for MMP zymogen processing, we found that arterial conditions did not affect the expression of MT-MMP-1, a cell-associated MMP activator, but that they significantly increased the levels of superoxide, another MMP activator, suggesting redox-dependent MMP processing. Additional experiments indicated that increased superoxide under arterial conditions was due to diminished scavenging by decreased extracellular superoxide dismutase. Arterial perfusion also stimulated cell proliferation (by 220% to 750%) in the majority of vein segments investigated. Our observations support the hypothesis that arterial hemodynamic conditions stimulate early vein graft remodeling. Furthermore, physiological arterial flow may work to prevent pathological remodeling, particularly the formation of intimal hyperplasia, through rapid inactivation of secreted MMPs and, possibly, through preferential stimulation of cell proliferation in the outer layers of the vein wall.

Measuring right ventricular function in the normal and hypertensive mouse hearts using admittance-derived pressure-volume loops

Mice are a widely used animal model for investigating cardiovascular disease. Novel technologies have been used to quantify left ventricular function in this species, but techniques appropriate for determining right ventricular (RV) function are less well demonstrated. Detecting RV dysfunction is critical to assessing the progression of pulmonary vascular diseases such as pulmonary hypertension. We used an admittance catheter to measure pressure-volume loops in anesthetized, open-chested mice before and during vena cava occlusion. Mice exposed to chronic hypoxia for 10 days, which causes hypoxia-induced pulmonary hypertension (HPH), were compared with control (CTL) mice. HPH resulted in a 27.9% increase in RV mass (P < 0.005), a 67.5% increase in RV systolic pressure (P < 0.005), and a 61.2% decrease in cardiac output (P < 0.05). Preload recruitable stroke work (PRSW) and slope of the maximum derivative of pressure (dP/dt(max))-end-diastolic volume (EDV) relationship increased with HPH (P < 0.05). Although HPH increased effective arterial elastance (E(a)) over fivefold (from 2.7 ± 1.2 to 16.4 ± 2.5 mmHg/μl), only a mild increase in the ventricular end-systolic elastance (E(es)) was observed. As a result, a dramatic decrease in the efficiency of ventricular-vascular coupling occurred (E(es)/E(a) decreased from 0.71 ± 0.27 to 0.35 ± 0.17; P < 0.005). Changes in cardiac reserve were evaluated by dobutamine infusion. In CTL mice, dobutamine significantly enhanced E(es) and dP/dt(max)-EDV but also increased E(a), causing a decrease in E(es)/E(a). In HPH mice, slight but nonsignificant decreases in E(es), PRSW, dP/dt(max)-EDV, and E(a) were observed. Thus 10 days of HPH resulted in RV hypertrophy, ventricular-vascular decoupling, and a mild decrease in RV contractile reserve. This study demonstrates the feasibility of obtaining RV pressure-volume measurements in mice. These measurements provide insight into ventricular-vascular interactions healthy and diseased states.

Four-dimensional flow assessment of pulmonary artery flow and wall shear stress in adult pulmonary arterial hypertension: results from two institutions.

To compare pulmonary artery flow using Cartesian and radially sampled four‐dimensional flow‐sensitive (4D flow) MRI at two institutions.