Rahn Ilsar

Abnormal Pulmonary Artery Stiffness in Pulmonary Arterial Hypertension: In Vivo Study with Intravascular Ultrasound

Background There is increasing recognition that pulmonary artery stiffness is an important determinant of right ventricular (RV) afterload in pulmonary arterial hypertension (PAH). We used intravascular ultrasound (IVUS) to evaluate the mechanical properties of the elastic pulmonary arteries (PA) in subjects with PAH, and assessed the effects of PAH-specific therapy on indices of arterial stiffness. Method Using IVUS and simultaneous right heart catheterisation, 20 pulmonary segments in 8 PAH subjects and 12 pulmonary segments in 8 controls were studied to determine their compliance, distensibility, elastic modulus and stiffness index β. PAH subjects underwent repeat IVUS examinations after 6-months of bosentan therapy. Results At baseline, PAH subjects demonstrated greater stiffness in all measured indices compared to controls: compliance (1.50±0.11×10–2 mm2/mmHg vs 4.49±0.43×10–2 mm2/mmHg, p<0.0001), distensibility (0.32±0.03%/mmHg vs 1.18±0.13%/mmHg, p<0.0001), elastic modulus (720±64 mmHg vs 198±19 mmHg, p<0.0001), and stiffness index β (15.0±1.4 vs 11.0±0.7, p = 0.046). Strong inverse exponential associations existed between mean pulmonary artery pressure and compliance (r2 = 0.82, p<0.0001), and also between mean PAP and distensibility (r2 = 0.79, p = 0.002). Bosentan therapy, for 6-months, was not associated with any significant changes in all indices of PA stiffness. Conclusion Increased stiffness occurs in the proximal elastic PA in patients with PAH and contributes to the pathogenesis RV failure. Bosentan therapy may not be effective at improving PA stiffness.

Measurement of pulmonary flow reserve and pulmonary index of microcirculatory resistance for detection of pulmonary microvascular obstruction

Background The pulmonary microcirculation is the chief regulatory site for resistance in the pulmonary circuit. Despite pulmonary microvascular dysfunction being implicated in the pathogenesis of several pulmonary vascular conditions, there are currently no techniques for the specific assessment of pulmonary microvascular integrity in humans. Peak hyperemic flow assessment using thermodilution-derived mean transit-time (Tmn) facilitate accurate coronary microcirculatory evaluation, but remain unvalidated in the lung circulation. Using a high primate model, we aimed to explore the use of Tmn as a surrogate of pulmonary blood flow for the purpose of measuring the novel indices Pulmonary Flow Reserve [PFR = (maximum hyperemic)/(basal flow)] and Pulmonary Index of Microcirculatory Resistance [PIMR = (maximum hyperemic distal pulmonary artery pressure)×(maximum hyperemic Tmn)]. Ultimately, we aimed to investigate the effect of progressive pulmonary microvascular obstruction on PFR and PIMR. Methods and Results Temperature- and pressure-sensor guidewires (TPSG) were placed in segmental pulmonary arteries (SPA) of 13 baboons and intravascular temperature measured. Tmn and hemodynamics were recorded at rest and following intra-SPA administration of the vasodilator agents adenosine (10–400 µg/kg/min) and papaverine (3–24 mg). Temperature did not vary with intra-SPA sensor position (0.010±0.009 v 0.010±0.009°C; distal v proximal; p = 0.1), supporting Tmn use in lung for the purpose of hemodynamic indices derivation. Adenosine (to 200 µg/kg/min) & papaverine (to 24 mg) induced dose-dependent flow augmentations (40±7% & 35±13% Tmn reductions v baseline, respectively; p<0.0001). PFR and PIMR were then calculated before and after progressive administration of ceramic microspheres into the SPA. Cumulative microsphere doses progressively reduced PFR (1.41±0.06, 1.26±0.19, 1.17±0.07 & 1.01±0.03; for 0, 104, 105 & 106 microspheres; p = 0.009) and increased PIMR (5.7±0.6, 6.3±1.0, 6.8±0.6 & 7.6±0.6 mmHg.sec; p = 0.0048). Conclusions Thermodilution-derived mean transit time can be accurately and reproducibly measured in the pulmonary circulation using TPSG. Mean transit time-derived PFR and PIMR can be assessed using a TPSG and adenosine or papaverine as hyperemic agents. These novel indices detect progressive pulmonary microvascular obstruction and thus have with a potential role for pulmonary microcirculatory assessment in humans.

MEASUREMENT OF PULMONARY FLOW RESERVE IN HIGHER PRIMATES

1 There are currently limited diagnostic methods for assessing the integrity of the pulmonary microvasculature. We hypothesized that a novel, invasively determined physiological index of ‘pulmonary flow reserve’ (PFR = maximal hyperaemic pulmonary blood flow divided by basal pulmonary flow) may facilitate microvascular assessment in the lung. Therefore, we developed a baboon model in which to: (i) validate the use of Doppler flow velocity for PFR assessment; (ii) define the optimal drug and dose regimen for attainment of maximal pulmonary hyperaemia; and (iii) demonstrate the feasibility of measuring PFR in healthy higher primates. 2 Doppler sensor guidewires were placed in segmental pulmonary arteries of 11 ketamine‐anaesthetized baboons. Vessel diameter, flow velocity and haemodynamics were recorded before and after direct intrapulmonary artery administration of saline, adenosine (50–500 µg/kg per min) and papaverine (3–60 mg), enabling calculation of PFR. 3 Saline (either bolus injection or infusion) did not alter vessel diameter or flow velocity (P > 0.1), validating local drug administration. Both adenosine and papaverine induced dose‐dependent increases in flow velocity from baseline (from 22.5 ± 2.3 to 32.7 ± 4.8 cm/s for 400–500 µg/kg per min adenosine; and from 23.9 ± 1.1 to 34.6 ± 4.0 cm/s for 24 mg papaverine; both P < 0.0001), without affecting pulmonary artery pressure or vessel diameter (P > 0.3). Healthy primate PFR values were 1.35 ± 0.10 and 1.39 ± 0.10 using 200 µg/kg per min adenosine and 24 mg papaverine, respectively (P > 0.8). 4 In conclusion, pulmonary flow reserve in higher primates can be assessed using Doppler sensor guidewire and either adenosine or papaverine as microvascular hyperaemic agents. Measurements of PFR may facilitate pulmonary microvascular assessments.

Bosentan and improved pulmonary endothelial function in pulmonary arterial hypertension

To the Editors: Pulmonary arterial hypertension (PAH) is characterised by pulmonary endothelial dysfunction and smooth muscle cell proliferation 1. Miniaturised catheter-based technology has recently enabled in vivo assessment of both endothelial dysfunction and pulmonary artery thickening in vivo 2, 3. Bosentan, an oral dual endothelin-1 receptor antagonist, has been shown to improve clinical outcomes in PAH 4. In vitro , bosentan has been shown to improve human endothelial cell function 5 and reduce neointimal and smooth muscle proliferation. In pigs in vivo , bosentan has been shown to partially restore hypoxia-induced reductions in nitric oxide 6. The effect of bosentan on human pulmonary artery structure and function in vivo , however, has not been studied. We hypothesised that bosentan therapy might improve pulmonary microvascular endothelial function and pulmonary artery remodelling in patients with established PAH. Therefore, we assessed the effect of 6 months of clinically indicated bosentan therapy in patients with advanced PAH on: 1) pulmonary microvascular function, assessed by Doppler-derived pulmonary blood flow responses to vasoactive agents; and 2) segmental pulmonary artery structure, measured by pulmonary intravascular ultrasound (IVUS). Eight bosentan-naive subjects (three males and five females; five subjects with idiopathic and three with scleroderma-related PAH; mean±sem age 66±4 yrs; weight 79±5 kg) were studied. The institutional review board (Royal Prince Alfred Hospital, Sydney, NSW, Australia) approved the study protocol and informed consent was obtained from all subjects. All patients were in New York Heart Association (NYHA) functional class III, had mean pulmonary arterial pressure ( P pa) >25 mmHg at rest (without demonstrable reversibility) and had pulmonary capillary wedge pressure ≤15 mmHg. Clinically indicated right heart catheterisation, assessing suitability for bosentan prescription, was performed. Thereafter, pulmonary artery IVUS assessment was performed in a distal segmental pulmonary artery of both upper and lower lobes …

Doppler-derived Pulmonary Flow Reserve Detects Pulmonary Microvascular Obstruction in High Primates

BACKGROUND Despite increasing evidence implicating the pulmonary microcirculation in the pathogenesis of lung conditions such as pulmonary vascular disease, there remain few methods for its evaluation in vivo. We recently demonstrated that the novel index of Doppler-derived pulmonary flow reserve (PFR(dopp)=maximal hyperaemic/basal pulmonary flow) could be reliably measured in high primates. Noting that the microvasculature is the chief regulator of pulmonary blood flow, we hypothesised that PFR(dopp) may detect microcirculatory loss. We therefore studied the relationship between PFR(dopp) and experimentally induced pulmonary microvascular obstruction using microspheres in higher primates. METHODS Under ketamine anaesthesia, Doppler sensor-guidewires were placed in the segmental pulmonary artery of three adult baboons. Doppler flow velocity and haemodynamics were recorded at rest and during hyperaemia [as induced by intrapulmonary artery adenosine (200 μg/kg/min)]. Serial PFR(dopp) evaluations were made after cumulative intrapulmonary artery ceramic microspheres administration. RESULTS Cumulative microsphere administration progressively reduced PFR(dopp) (1.54 ± 0.26, 1.48 ± 0.20, 1.12 ± 0.04 and 1.18 ± 0.09; baseline, 10(4), 10(5) and 10(6) microspheres boluses; p<0.02) without affecting pulmonary artery pressure, systemic artery pressure or heart rate. CONCLUSIONS Doppler-derived PFR can detect partial, progressive pulmonary microvascular obstruction in higher primates. PFR(dopp) may thus have a potential role in the assessment of the pulmonary microcirculation in vivo.