Physiological aspects of cardiopulmonary dysanapsis on exercise in adults born preterm

Abstract

Progressive improvements in perinatal care and respiratory management of preterm infants have resulted in increased survival of newborns of extremely low gestational age over the past few decades. However, the incidence of bronchopulmonary dysplasia, the chronic lung disease after preterm birth, has not changed. Studies of the long-term follow-up of adults born preterm have shown persistent abnormalities of respiratory, cardiovascular and cardiopulmonary function, possibly leading to a lower exercise capacity. The underlying causes of these abnormalities are incompletely known, but we hypothesize that dysanapsis, i.e. discordant growth and development, in the respiratory and cardiovascular systems is a central structural feature that leads to a lower exercise capacity in young adults born preterm than those born at term. We discuss how the hypothesized system dysanapsis underscores the observed respiratory, cardiovascular and cardiopulmonary limitations. Specifically, adults born preterm have: (1) normal lung volumes but smaller airways, which causes expiratory airflow limitation and abnormal respiratory mechanics but without impacts on pulmonary gas exchange efficiency; (2) normal total cardiac size but smaller cardiac chambers; and (3) in some cases, evidence of pulmonary hypertension, particularly during exercise, suggesting a reduced pulmonary vascular capacity despite reduced cardiac output. We speculate that these underlying developmental abnormalities may accelerate the normal age-associated decline in exercise capacity, via an accelerated decline in respiratory, cardiovascular and cardiopulmonary function. Finally, we suggest areas of future research, especially the need for longitudinal and interventional studies from infancy into adulthood to better understand how preterm birth alters exercise capacity across the lifespan.

Keywords: bronchopulmonary dysplasia; cardiac development; exercise physiology; extremely low gestational age newborns; lung development; prematurity; pulmonary hypertension.

Figure 1:. Aerobic exercise capacity is reduced in young adults born preterm.

Forest plot generated via Review Manager demonstrating a lesser aerobic exercise capacity (VO₂max; mL/kg/min) in young adults born preterm (preterm) compared to their counterparts born at term (term). These are pooled data from various studies in adults that reported VO₂max in their results (Huckstep et al., 2020; Vrijlandt et al., 2006; Debevec et al., 2019; Haraldsdottir et al., 2019; Goss et al., 2018; Caskey et al., 2016; Duke et al., 2019; Farrell et al., 2015; Lovering et al., 2014; Clemm et al., 2014). Data are organized from latest to earliest mean gestational age reported in each study. Gestational age was averaged for those studies that separated the preterm group into those that did or did not have bronchopulmonary dysplasia. The N column represents the respective sample size of each study. The age range of the participants, at the time of study, of the included studies was 19–28 years, obtained from mean data reported. Mean differences and 95% confidence intervals were computed using the inverse variance weighting method. The red square and red dashed line represent the difference of pooled preterm and term-born data from studies included in the analysis. In the studies included, there was an overall statistical effect with preterm having a lower VO₂max than term.

Figure 2:. Cardiopulmonary factors limiting aerobic exercise capacity in term and preterm adults.

Schematic representation of the factors limiting aerobic exercise capacity (VO₂max/peak in mL/kg/min) in (A) untrained adults born at term and (B) untrained adults born preterm. In those born at term, there is normal cardiopulmonary dysanapsis and, thus, an “overbuilt” pulmonary system (lungs + vasculature). This means that the respiratory system of the untrained, term-born adult is not a limiting factor as evidence by little/no mechanical ventilatory constraints and a minimal change in P_PA and PVR, neither of which limit Q_T. Despite an appropriate cardiovascular system, Q_T limits aerobic exercise capacity in untrained adults born at term. Conversely, in the adult born preterm, excessive/abnormal respiratory, cardiopulmonary, and cardiovascular dysanapsis leads to multiple factors contributing (in heterogeneous proportions) to reduced aerobic exercise capacity. The * denotes a factor that impairs/limits aerobic exercise capacity. Green text represents a physiologic attribute that is exceptional/overbuilt, blue text represents an attribute that is considered to be normal, and red text represents an attribute that is reduced/impaired. For flow-volume loop schematic, the black line represents the maximum flow-volume loop generated from a forced expiration, the red dashed line represents the resting tidal flow-volume loop, and the blue line represents the exercise flow-volume loop. Abbreviations: EFL = expiratory flow limitation; LV = left ventricle; P_PA = pulmonary artery pressure; PVR = pulmonary vascular resistance; Q_T = cardiac output; RV = right ventricle.