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Right Ventricular Longitudinal Strain Is Depressed in a Bovine Model of Pulmonary Hypertension

Bartels, Karsten, MD; Brown, R. Dale, PhD; Fox, Daniel L., MD; Bull, Todd M., MD; Neary, Joseph M., VetMB, PhD; Dorosz, Jennifer L., MD; Fonseca, Brian M., MD; Stenmark, Kurt R., MD

doi: 10.1213/ANE.0000000000001215
Cardiovascular Anesthesiology: Research Report
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BACKGROUND: Pulmonary hypertension and resulting right ventricular (RV) dysfunction are associated with significant perioperative morbidity and mortality. Although echocardiography permits real-time, noninvasive assessment of RV function, objective and comparative measures are underdeveloped, and appropriate animal models to study their utility are lacking. Longitudinal strain analysis is a novel echocardiographic method to quantify RV performance. Herein, we hypothesized that peak RV longitudinal strain would worsen in a bovine model of pulmonary hypertension compared with control animals.

METHODS: Newborn Holstein calves were randomly chosen for induction of pulmonary hypertension versus control conditions. Pulmonary hypertension was induced by exposing animals to 14 days of hypoxia (equivalent to 4570 m above sea level or 430 mm Hg barometric pressure). Control animals were kept at ambient pressure/normoxia. At the end of the intervention, transthoracic echocardiography was performed in awake calves. Longitudinal wall strain was analyzed from modified apical 4-chamber views focused on the RV. Comparisons between measurements in hypoxic versus nonhypoxic conditions were performed using Student t test for independent samples and unequal variances.

RESULTS: After 14 days at normoxic versus hypoxic conditions, 15 calves were examined with echocardiography. Pulmonary hypertension was confirmed by right heart catheterization and associated with reduced RV systolic function. Mean systolic strain measurements were compared in normoxia-exposed animals (n = 8) and hypoxia-exposed animals (n = 7). Peak global systolic longitudinal RV strain after hypoxia worsened compared to normoxia (−10.5% vs −16.1%, P = 0.0031). Peak RV free wall strain also worsened after hypoxia compared to normoxia (−9.6% vs −17.3%, P = 0.0031). Findings from strain analysis were confirmed by measurement of tricuspid annular peak systolic excursion.

CONCLUSIONS: Peak longitudinal RV strain detected worsened RV function in animals with hypoxia-induced pulmonary hypertension compared with control animals. This relationship was demonstrated in the transthoracic echocardiographic 4-chamber view independently for the RV free wall and for the combination of the free and septal walls. This innovative model of bovine pulmonary hypertension may prove useful to compare different monitoring technologies for the assessment of early events of RV dysfunction. Further studies linking novel RV imaging applications with mechanistic and therapeutic approaches are needed.

Published ahead of print March 11, 2016

From the *Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado; Cardiovascular Pulmonary Research and Developmental Lung Biology Laboratories, University of Colorado School of Medicine, Aurora, Colorado; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado; §Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado; Department of Animal and Food Sciences, Texas Tech University, Lubbock, Texas; and Department of Cardiology, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado.

Accepted for publication January 6, 2016.

Published ahead of print March 11, 2016

Funding: This work was supported by National Institutes of Health grants R01-HL114887, P01-HL014985, and R01-HL125827 (to KRS).

The authors declare no conflicts of interest.

Preliminary results of this work were presented in an abstract form at the American Heart Association 2012 Scientific Sessions in Los Angeles, CA.

Reprints will not be available from the authors.

Address correspondence to Karsten Bartels, MD, Department of Anesthesiology, University of Colorado Denver, School of Medicine, 12401 E. 17th Ave., Leprino Office Bldg., 7th Floor, MS B-113, Aurora, CO 80045. Address e-mail to karsten.bartels@ucdenver.edu.

Pulmonary hypertension and subsequent right ventricular (RV) dysfunction remain a significant challenge for the perioperative clinician.1–5 Indeed, in a retrospective study of pulmonary hypertension patients undergoing noncardiac surgery, 42% suffered significant morbidity and 7% died within 30 days postoperatively.6 Similarly, after coronary artery bypass surgery, pulmonary hypertension was associated with a >2-fold increased mortality.7 Early intervention for the treatment of RV dysfunction in the context of pulmonary hypertension is highly dependent on its prompt diagnosis. Although echocardiography is a valuable tool to assess cardiac function, quantitative metrics to assess RV function are far less developed than for the left ventricle (LV).8 Accordingly, there is a great need to develop and validate echocardiographic measures to eventually enable rational echo-guided therapy of RV dysfunction.

Commonly, RV systolic function is described as normal versus mildly, moderately, or severely reduced based on qualitative visual impression.9 Reliance solely on such nonstandardized assessments for RV systolic function is discouraged in recent guidelines.9 Alternative, quantitative approaches for estimation of RV function include RV fractional area change, RV ejection fraction, the rise of the RV to right atrial pressure gradient during systole (dP/dt), tricuspid annular plane systolic excursion (TAPSE), or the RV myocardial performance index (Tei-Index).10 Speckle tracking is a more recent technology, which enables quantification of regional myocardial strain. Peak longitudinal RV strain permits evaluation of RV contractile function in a quantitative fashion and independent of the ultrasound angle of incidence on the structure of interest.

Although declining RV strain has already been associated with poorer outcomes in clinical studies of pulmonary hypertension patients,11 its utility to impact patient outcomes remains unproven.12 Transformation of advanced RV echocardiographic imaging from a descriptive method into a tool to drive mechanism-based therapy will require large animal models that enable more seamless translation to clinical practice than is afforded by current rodent models.13 In a first step to establish such a model, we hypothesized that RV longitudinal systolic strain is depressed, reflecting declining RV performance, in a bovine model of hypoxia-induced pulmonary hypertension compared with control animals. In addition, we used cardiac magnetic resonance imaging (MRI) as a “gold standard” to determine RV systolic function in a second cohort of calves exposed to hypoxia versus normoxia.

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METHODS

Induction of Pulmonary Hypertension

All animal experiments were performed after Institutional Animal Care and Use Committee approval. Experiments conformed to the National Institutes of Health Guide for the care and use of laboratory animals.14 Induction of pulmonary hypertension was performed as described previously.15,16 Briefly, 15 newborn male Holstein dairy calves were randomly chosen to be exposed to hypoxia or normoxia. Hypoxia was induced by nitrogen dilution or hypobaric hypoxia to the equivalent of 4570 m above sea level or 430 mm Hg for 14 days. Control animals were studied after spending 14 days at ambient pressure and oxygen levels.

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Hemodynamic Measurements

Hemodynamic assessments were made in awake animals as previously described.17 Briefly, for the hemodynamic measurements, an internal jugular venous introducer catheter was first placed with local anesthesia. Next, a balloon-tipped catheter was floated into the pulmonary artery via the introducer, and its position was confirmed through visual analysis of the transduced pressure waveform.

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Echocardiography

Figure 1

Figure 1

Figure 2

Figure 2

Transthoracic echocardiography was performed in awake animals, manually restrained in lateral recumbency, with a General Electric Vivid 5 (General Electric Co., Cleveland, OH) echocardiography machine with concurrent 3-lead electrocardiogram. To improve image quality, the animals were routinely shaved over the right and left chest. RV images were obtained using an apical RV-focused 4-chamber view (Fig. 1). Analysis of peak systolic RV strain was performed offline using a General Electric Echo Pacs® version 3.0 software packet (Fig. 2). Briefly, the RV endocardium was traced starting at the RV septal annulus, via the approximated RV apex, to the lateral annulus in the apical 4-chamber view. Speckle tracking occurred in 6 segments of the RV myocardium, and thickness of the tracked zone was adjusted as needed to include only myocardium. Negative strain values reflect tissue shortening/contraction, whereas positive strain values indicate tissue lengthening/relaxation. Hence, a less negative systolic strain value indicates poorer RV systolic function compared with a more negative strain value.18 TAPSE19 was calculated from the maximum systolic displacement of the lateral basal segment of the tricuspid annulus.

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Cardiac MRI

MRI examinations were performed in mechanically ventilated calves under general anesthesia with isoflurane (1.5%–2%). Subambient oxygen concentrations (10%) were used for the pulmonary hypertension calves. A 1.5 Tesla GE Signa MRI scanner (General Electric Healthcare, Milwaukee, WI) was used. Cardiac functional imaging was performed with retrospective pulse gating, using segmented steady-state free precession technique and included a vertical long-axis, horizontal short-axis, and short-axis stack. Typical scan parameters were field of view = 40–45 cm, slice thickness = 8 mm, number of excitations = 4 (free breathing), echo time/repetition time = 1.6/3.9, and in-plane resolution = 1.4–1.6 mm. Temporal resolution was 20 to 30 ms. RV volumes and ejection fractions were assessed by standard planimetry techniques using computer software (QMASS v.7.5, Medis Medical Imaging Systems, Netherlands).

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Blinding and Randomization

All echocardiographic assessments were made in duplicate by independent echocardiographers blinded to the hypoxia/normoxia group allocation. Analysis was performed in a random order by attaching a randomly generated number (Excel, Microsoft Co., Redmond, WA) to the animal ID number and then generating a list ordered according to the value of the associated random number.

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Statistical Analysis

An observed relative reduction of global RV longitudinal strain of 34.5% reported in a clinical study comparing pulmonary hypertension patients with control patients informed the sample size estimate.20 For the primary outcome of this study (RV peak longitudinal strain), a sample size of 14 (n = 7 per group) would yield 78% power to detect a 30% relative difference in strain and 95% power for to detect a 40% relative difference.21 Continuous outcome variables for groups with n = 3 were analyzed using unpaired Student t test with a 2-tailed P value of <0.05 considered significant.22 For groups with n ≥ 7, the Shapiro-Wilk test was used to assess normal distribution of residuals. Differences in means for continuous variables were assessed with Student t test for independent samples and unequal variances. The probability that a random observation from the hypoxia group was different than a random observation from the normoxia group was also assessed using the independent samples Mann-Whitney U test.23 The Wilcoxon-Mann-Whitney P values are exact.

For categorical variables, statistical significance was determined using Fisher exact test. Correlation of mean pulmonary artery pressures with echocardiographic parameters was assessed using Pearson correlation. Statistical significance was assumed at a 2-tailed P value of <0.05. Interrater reliability was assessed by intraclass correlation coefficient (ICC) reporting confidence intervals (CIs). SPSS® version 23 (IBM Corp., Armonk, NY) was used for statistical analysis.

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RESULTS

Exposure of newborn Holstein calves to 2 weeks of hypoxia compared with ambient oxygen levels has previously been shown to result in markedly reduced arterial oxygen content: In hypoxic versus normoxic calves, means (SD) for systemic arterial oxygen partial pressures were 29 (5) vs 66 (4) mm Hg and for oxygen saturation were 56 (14)% vs 88 (4)%.17 Hypoxia-exposed calves in our study reliably developed pulmonary hypertension without significant tricuspid regurgitation. Right heart catheterization demonstrated a mean pulmonary artery pressure of 26 mm Hg in normoxia compared with 111 mm Hg in hypoxic animals (P = 0.0003) as shown in Table 1. TAPSE was reduced in animals exposed to hypoxia (Table 1), consistent with RV dysfunction. Qualitative assessments of RV systolic function using conventional 2-dimensional echocardiography without quantitative measurements by 2 blinded echocardiographers are reported in Table 2. RV function was found to be qualitatively reduced in the hypoxic compared with the normoxic group (rater 1: P = 0.0427; rater 2: P = 0.0014). Septal flattening/distortion was more prevalent in the hypoxic group (P = 0.0101 for both raters).

Table 1

Table 1

Table 2

Table 2

The results of RV strain analysis in normoxic and hypoxic animals are shown in Figures 3 and 4. Peak longitudinal RV strain, as evaluated from the analysis of transthoracic echocardiographic images using a 4-chamber view, was depressed in calves exposed to 2 weeks of hypoxia compared with normoxic calves. This relationship held true both when analyzing combined peak systolic longitudinal strain in the free and septal wall of the RV (Fig. 3) and for dedicated analysis of strain in the free wall only (Fig. 4). Peak systolic strain rates in hypoxic versus normoxic animals were not statistically different: −1.8 (0.4)/s vs −1.5 (0.4)/s (P = 0.28) for combined and −2.0 (0.4)/s vs −1.7 (0.5)/s (P = 0.18) for free wall-only analysis. Benchmark parameters of RV and LV function were assessed using cardiac MRI in a separate cohort of normoxia- and hypoxia-exposed animals (n = 3 each), and results are shown in Table 3.

Table 3

Table 3

Figure 3

Figure 3

Figure 4

Figure 4

The Pearson correlation coefficient between RV strain and mean pulmonary artery pressure was 0.65 (P = 0.0086) and 0.66 (P = 0.0076) for combined and free wall-only, strain respectively. The correlation coefficient between the average qualitative assessment of RV systolic function by the 2 raters and RV strain was 0.73 (P = 0.0020) for combined and 0.68 (P = 0.0049) for free wall-only strain.

Interrater reliability was assessed by ICC using a 98.3% CI to account for comparisons of 3 correlated end points: ICC = 0.88 (98.3% CI, 0.53–0.97) for combined RV free and septal wall peak longitudinal strain, ICC = 0.94 (98.3% CI, 0.78–0.98) for RV free wall peak longitudinal strain, and ICC = 0.88 (98.3% CI, 0.53–0.97) for qualitative analysis of RV function. Conservatively applying ICC cutoffs to the lower limit of the 98.3% CI, we used the following scale for assessment of agreement: <0.4 indicates poor agreement between raters, 0.40 to 0.59 indicates fair agreement, 0.60 to 0.74 indicates good agreement, and 0.75 to 1.0 indicates excellent agreement. For RV free wall, peak longitudinal strain agreement was excellent, and for combined RV free and septal wall peak longitudinal strain and for qualitative analysis of RV function, agreement was fair.

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DISCUSSION

In an established and well-validated bovine model of hypoxia-induced pulmonary hypertension, transthoracic echocardiography was successfully used to detect reduced RV function. In addition to conventional, qualitatively assessed echocardiographic RV systolic function assessments, peak systolic longitudinal strain was impaired in calves exposed to hypoxia.

Echocardiographic longitudinal strain encompasses all segments of the RV depicted in a 4-chamber view as opposed to only quantifying the motion of the lateral annulus, as is usually done for TAPSE. In this sense, longitudinal RV strain analysis combines advantages of conventional 2-dimensional echocardiographic global RV function assessment using multiple segments with the quantitative measurement that is obtained from TAPSE. Our hypothesis that calves exposed to 2 weeks of hypoxia would exhibit depressed peak longitudinal RV strain was confirmed. Reduced RV ejection fraction found in anesthetized hypoxic animals using cardiac MRI is consistent with reduced systolic function detected from peak RV longitudinal strain analysis in awake animals. This work represents the application of a novel quantitative echocardiographic approach to RV evaluation in an innovative large animal model of progressive pulmonary hypertension induced by exposure to chronic hypoxia.

Although the RV is commonly described as “crescent shaped” or “boot shaped,” its structure is too complex to be condensed into a single attribute.8 Indeed, in an attempt to address the limited knowledge on quantitative assessment of RV function compared with LV function, the National Heart Lung and Blood Institute convened a working group to advance our knowledge on how to measure and detect RV dysfunction.24 For the assessment of RV function, 2-dimensional longitudinal strain appears reproducible and feasible.25 Strain is defined as the change in length of the myocardium over time compared with its baseline length at end diastole.25 Because the septum is often assumed to contribute mostly to LV systolic function, RV longitudinal strain can be derived from the free wall alone or from both the free wall and the septum.26

Other large animal models to evaluate RV strain often rely on surgical banding of the pulmonary venous drainage27 or pulmonary artery banding28 to induce pulmonary hypertension. Aguero et al.27 using a pig model of pulmonary vein banding via thoracotomy similarly found worsened RV longitudinal strain in the pigs with induced pulmonary hypertension. By contrast, our model used hypoxia-induced pulmonary hypertension and avoided confounding traumatic inflammatory responses commonly observed after even minor animal surgery.29 Hence, this approach may be particularly translatable to patients with congenital heart disease, chronic obstructive pulmonary disease, or alveolar hypoventilation collectively arising from group 3 pulmonary hypertension,30 which is the most numerically abundant form of pulmonary hypertension.

Although worsened RV longitudinal strain has been associated with worse outcomes in pulmonary hypertension and heart failure, including in patients who underwent LV assist device surgery,31–34 the most sensitive and specific method for detection of RV dysfunction remains unknown. Our model is ideally suited to observe the early onset and temporal progression of RV failure that can be monitored using noninvasive indices of RV function such as RV longitudinal strain. Finally, this neonatal model will be uniquely relevant to study pediatric pulmonary hypertension, where altered hemodynamic load occurs in the developmental context of the transition of the RV to postnatal life.35

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LIMITATIONS

The strain measurements were performed in spontaneously breathing, awake animals. Given that echocardiographic strain measurements are load dependent, positive pressure ventilation as was required for cardiac MRI may have altered loading conditions. In addition, normal strain values in humans and cows differ: A meta-analysis of strain measurements in children reported a normal value of −29.03% for RV global longitudinal strain.36 This compares with −16.1% for combined and −17.3% for free wall peak longitudinal RV strain in normoxic neonatal calves in our study. Further, this study did not include all modalities for assessment of RV function. Although we did measure pulmonary artery pressures and assessed RV systolic function qualitatively using 2-dimensional echocardiography, TAPSE, and cardiac MRI, we did not include measures such as radial strain,37 myocardial performance index, or 3-dimensional echocardiographic measurements to evaluate RV function. This indeed is a critical need and, therefore, will be the focus of a future study, where we will compare performance of different echocardiographic indices of RV assessment at different time points during induction of pulmonary hypertension. Our model is ideally suited for such a study because the exposure to hypoxia induces pulmonary hypertension gradually.

In conclusion, we found peak longitudinal RV strain obtained via transthoracic echocardiography to be depressed in a bovine model of induced pulmonary hypertension. Reflective of the RV response to higher pulmonary vascular resistance and increased pulmonary artery pressures, longitudinal strain is an objective measure of RV function that is independent of the ultrasound beam angle of incidence. Therefore, it may be especially advantageous in the perioperative environment. Identifying the most sensitive and specific tools for assessment of RV function at an early stage of disease may prove useful when testing interventions to avoid or reverse RV failure.

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DISCLOSURES

Name: Karsten Bartels, MD.

Contribution: This author helped design the study, conduct the study, collect and analyze the data, and write the manuscript.

Attestation: Karsten Bartels approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: R. Dale Brown, PhD.

Contribution: This author helped design the study, conduct the study, collect and analyze the data, and write the manuscript.

Attestation: R. Dale Brown approved the final manuscript.

Name: Daniel L. Fox, MD.

Contribution: This author helped conduct the study, and collect and analyze the data.

Attestation: Daniel L. Fox approved the final manuscript.

Name: Todd M. Bull, MD.

Contribution: This author helped design the study, and write the manuscript.

Attestation: Todd M. Bull approved the final manuscript.

Name: Joseph M. Neary, VetMB, PhD.

Contribution: This author helped design the study, conduct the study, and collect the data.

Attestation: Joseph M. Neary approved the final manuscript.

Name: Jennifer L. Dorosz, MD.

Contribution: This author helped design the study, conduct the study, and collect the data.

Attestation: Jennifer L. Dorosz approved the final manuscript.

Name: Brian M. Fonseca, MD.

Contribution: This author helped design the study, conduct the study, collect the data, and prepare the manuscript.

Attestation: Brian M. Fonseca approved the final manuscript.

Name: Kurt R. Stenmark, MD.

Contribution: This author secured funding for the study, and helped design the study, conduct the study, collect and analyze the data, and prepare the manuscript.

Attestation: Kurt R. Stenmark approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript. Kurt R. Stenmark is the archival author.

This manuscript was handled by: Charles W. Hogue, MD.

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ACKNOWLEDGMENTS

The authors thank Dr. William Henderson, PhD, MPH, Professor, Department of Biostatistics and Informatics, University of Colorado School of Public Health, Aurora, Colorado, for assistance with the statistical analysis.

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