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.
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
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.
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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