Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia

Abstract

Chesler N. Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia. J Appl Physiol 117: 833-839, 2014. First published August 28, 2014 doi:10.1152/japplphysiol.00059.2014.-Chronic hypoxia causes chronic mountain sickness through hypoxiainduced pulmonary hypertension (HPH) and increased hematocrit. Here, we investigated the impact of increased hematocrit and HPH on right ventricular (RV) afterload via pulmonary vascular impedance. Mice were exposed to chronic normobaric hypoxia (10% oxygen) for 10 (10H) or 21 days (21H). After baseline hemodynamic measurements, ϳ500 l of blood were extracted and replaced with an equal volume of hydroxyethylstarch to normalize hematocrit and all hemodynamic measurements were repeated. In addition, ϳ500 l of blood were extracted and replaced in control mice with an equal volume of 90% hematocrit blood. Chronic hypoxia increased input resistance (Z 0 increased 82% in 10H and 138% in 21H vs. CTL; P Ͻ 0.05) and characteristic impedance (Z C increased 76% in 10H and 109% in 21H vs. CTL; P Ͻ 0.05). Hematocrit normalization did not decrease mean pulmonary artery pressure but did increase cardiac output such that both Z 0 and ZC decreased toward control levels. Increased hematocrit in control mice did not increase pressure but did decrease cardiac output such that Z 0 increased. The paradoxical decrease in ZC with an acute drop in hematocrit and no change in pressure are likely due to inertial effects secondary to the increase in cardiac output. A novel finding of this study is that an increase in hematocrit affects the pulsatile RV afterload in addition to the steady RV afterload (Z 0). Furthermore, our results highlight that the conventional interpretation of Z C as a measure of proximal artery stiffness is not valid in all physiological and pathological states. cardiopulmonary hemodynamics; chronic hypoxia; characteristic impedance; blood viscosity; pulmonary vascular impedance CHRONIC MOUNTAIN SICKNESS (CMS), also known as Monge's disease, occurs after chronic exposure to hypoxia at high altitudes and is characterized by increased pulmonary artery pressures and pulmonary vascular resistance (29) as well as increased hematocrit (19). Chronic hypoxia also contributes to worse outcomes in lung diseases such as chronic obstructive pulmonary disease, sleep apnea, and pulmonary fibrosis (1,10,15). In preclinical animal models of pulmonary arterial hypertension (PAH), chronic hypoxia is often used to generate hypoxia-induced pulmonary hypertension (HPH). PAH is a debilitating disease with a low median survival of 2.8 yr (6,17) and is characterized by remodeling throughout the pulmonary vasculature, including distal arterial narrowing and proximal and distal pulmonary artery stiffening, leading to right ventricular (RV) dysfunction that progresses to RV failure as the cause of death (28). HPH in rodents recapitulates the pulmonary vascular remodeling and RV hypertrophy that occur in patients with PAH but also increases hematocrit. Indeed, the increase in ...

Increased Red Blood Cell Stiffness Increases Pulmonary Vascular Resistance and Pulmonary Arterial Pressure

“…However, as discussed in Ref. [20], Z C depends not only on proximal artery stiffness (with an inverse square root relationship) but also on blood inertance in the proximal arteries (with a square root relationship). The decrease in CO found here decreases inertance, which likely explains the decrease in Z C .…”

“…Mice were instrumented for PVZ measurements as previously described [20,21]. In brief, mice were anesthetized with urethane (2 mg/g body weight), intubated and placed on a ventilator using a tidal volume of $225 ll and respiratory rate of $200 breaths/min of room air.…”

“…Pressure tracings were recorded at 5 kHz on a custom hemodynamic workstation (Cardiovascular Engineering, Norwood, MA). Measurement of blood flow velocity and main PA inner diameter were performed via ultrasound (Visualsonics, Toronto, ON, Canada) with a 40 MHz probe during the surgery and recorded with our custom system as done previously; volumetric flow rate (Q) was calculated using velocity time integral and main PA inner diameter measurements obtained via long axis view [20,21].…”

“…Data obtained during our experiments were analyzed as previously described [20,21] using our custom software and hemodynamic workstation (Cardiovascular Engineering, Norwood, MA). In brief, our software used electrocardiogram as a fixed standard of reference for the Q and P waveforms, which then processed and analyzed our data accordingly.…”

“…In brief, our software used electrocardiogram as a fixed standard of reference for the Q and P waveforms, which then processed and analyzed our data accordingly. All equations used henceforth can be found in these previous publications [20,21], including but not limited to PVR Z 0 , characteristic impedance Z C , pulmonary arterial compliance Ca, wave reflections RQ, and pulse wave velocity (PWV). Note: Values are means 6 SE; n ¼ 11 baseline, first, second, and third blood replacements.…”