Physiological Stress Elicits Impaired Left Ventricular Function in Preterm-Born Adults

Background Experimental and clinical studies show that prematurity leads to altered left ventricular (LV) structure and function with preserved resting LV ejection fraction (EF). Large-scale epidemiological data now links prematurity to increased early heart failure risk. Objectives The authors performed echocardiographic imaging at prescribed exercise intensities to determine whether preterm-born adults have impaired LV functional response to physical exercise. Methods We recruited 101 normotensive young adults born preterm (n = 47; mean gestational age 32.8 ± 3.2 weeks) and term (n = 54) for detailed cardiovascular phenotyping. Full clinical resting and exercise stress echocardiograms were performed, with apical 4-chamber views collected while exercising at 40%, 60%, and 80% of peak exercise capacity, determined by maximal cardiopulmonary exercise testing. Results Preterm-born individuals had greater LV mass (p = 0.015) with lower peak systolic longitudinal strain (p = 0.038) and similar EF to term-born control subjects at rest (p = 0.62). However, by 60% exercise intensity, EF was 6.7% lower in preterm subjects (71.9 ± 8.7% vs 78.6 ± 5.4%; p = 0.004) and further declined to 7.3% below the term-born group at 80% exercise intensity (69.8 ± 6.4% vs 77.1 ± 6.3%; p = 0.004). Submaximal cardiac output reserve was 56% lower in preterm-born subjects versus term-born control subjects at 40% of peak exercise capacity (729 ± 1,162 ml/min/m2 vs. 1,669 ± 937 ml/min/m2; p = 0.021). LV length and resting peak systolic longitudinal strain predicted EF increase from rest to 60% exercise intensity in the preterm group (r = 0.68, p = 0.009 and r = 0.56, p = 0.031, respectively). Conclusions Preterm-born young adults had impaired LV response to physiological stress when subjected to physical exercise, which suggested a reduced myocardial functional reserve that might help explain their increased risk of early heart failure. (Young Adult Cardiovascular Health sTudy [YACHT]; NCT02103231)

P reterm birth rates range from 5% to 18% worldwide (1). The population of adults born preterm has risen sharply in recent decades because modern perinatal care often achieves 95% survival rates (2).
Multiple studies have described a distinct preterm cardiovascular phenotype, including altered cardiac structure and function (3)(4)(5) and impaired exercise capacity (6), as well as increased risk for hypertensive disorders and stroke (7). However, as the modern cohorts of preterm-born survivors now approach middle age, the long-term epidemiological consequences of prematurity remain largely unknown. A recently reported study of >2.6 million individuals born between 1987 and 2012 identified preterm birth as a novel risk factor for incident heart failure in childhood and adolescence (8), emphasizing the importance of research into the underlying mechanisms responsible for increased risk in this population.
Acute cardiac insufficiency is uncommon in young adults (9) and a previous cardiovascular magnetic resonance (CMR) study confirmed that preterm-born young adults maintain a fully preserved resting left ventricular (LV) ejection fraction (EF) despite significant functional and anatomical LV remodeling (4).
Stress echocardiography is a powerful tool used to unmask underlying cardiac dysfunction that is well-compensated at rest by assessing the cardiac response to physiological stressors such as exercise (10). Because those born preterm have well compensated resting LV function despite significant structural modifications and moderate changes in myocardial deformation at rest (4), investigating cardiac functional responses to physiological stress is essential to more fully understand the impact of being born preterm on LV function (10). We therefore used 2-dimensional echocardiography to test the hypothesis that the LV of preterm-born young adults has reduced myocardial reserve that results in functional impairment in response to the physiological stressor of physical exercise.  Insulin resistance was calculated using the homeostasis model assessment calculator (11).    S t r e s s e c h o c a r d i o g r a p h y . After completing CPET testing, participants had a 30-min recovery period during which they were offered water and an additional cereal bar. Submaximal exercise stress echocardiography was then performed on study subjects for 3 min at 40%, 60%, and 80% of their peak exercise wattage achieved during CPET testing.

METHODS
After participants exercised at each prescribed workload for 2 min, and steady-state heart rate was verified, apical 4-chamber views oriented for optimal imaging of the LV and pulsed wave Doppler imaging of mitral inflow were collected at each stage using either a Philips iE33 or Philips EPIQ 7C cardiology ultrasound machine (Philips Healthcare, Surrey, United Kingdom). Participants were given a 3-min rest period between each stage. Off-line image analysis was only performed on images in which heart rate was within 5% of maximum achieved steadystate heart rate for a given stage.         Preterm-born young adults (orange) had a lower ejection fraction (EF) than term-born young adults (blue) at 60% and 80% of peak exercise intensity (71.9 AE 8.7% vs. 78.6 AE 5.4% and 69.8 AE 6.4% vs. 77.1 AE 6.3%, respectively; p < 0.005). In the preterm group, EF at 60% and 80% exercise intensity were both significantly lower than the within-group EF at 40% intensity (3.7% and 5.8% lower, respectively; p < 0.05). This declining EF with increasing exercise intensity was not observed in term-born control subjects. Error bars represent SEM.
*Significantly lower EF than that in the term-born group (p < 0.005). †Significantly lower than the within-group EF at 40% (p < 0.05).
these parameters against the change in EF from rest to 60% exercise load (

DISCUSSION
This study demonstrated for the first time that preterm-born young adults had a significantly impaired LV systolic response to physical exercise stress.
Structurally, echocardiography revealed that prematurity was associated with greater LV mass and lower LV volumes indexed for body size, as previously shown by CMR (4). At rest, EF remained fully preserved, but increasing exercise intensity elicited a decline in EF, resulting in an overall lower EF than term-born control subjects. Submaximal COR was also lower, and LV length and degree of prematurity were highly predictive of this adverse systolic response in preterm-born individuals.

POTENTIAL MECHANISTIC LINKS BETWEEN
PRETERM BIRTH AND HEART FAILURE. Recent largescale epidemiological data provided evidence that being born preterm increased the risk of early heart failure (8). In line with this, preterm experimental models in rats showed prematurity-related stress could elicit LV remodeling and impaired systolic function before blood pressure elevation. Moreover, these early cardiac alterations increased susceptibility to developing heart failure secondary to the insult of persistent hemodynamic overload induced by angiotensin II infusion (17,18).
It is consequential that the systolic deficits we observed manifested under moderate intensity physical exercise and were clearly evident in this cohort of healthy, normotensive, preterm-born young adults, which indicated that, apart from subsequent pathology or insult, prematurity alone confers this systolic impairment and diminished myocardial There was a wide gestational age range in our participants, with most of our preterm-born individuals born moderate to late preterm, which reflected the demographic characteristics of the general preterm population (28). Although this made our findings more relevant to a larger proportion of the population, larger studies will be needed to fully explore to what extent the severity of the LV systolic response to exercise is altered specifically in very and extreme preterm-born adults.
Resting echocardiography was performed per clinical standards with subjects scanned in the lateral decubitus position (12); however, upright cycle ergometry and treadmill are the most common clinical exercise stress modalities (29). We selected upright, seated cycle ergometry for CPET and stress echocardiography to align with clinical norms and to also minimize torso movement during scanning. Although all participants received standardized, per-protocol measurements, the differing posture could confound the direct comparisons of some resting echocardiography versus exercise echocardiography measures, such as stroke volume (30).

CONCLUSIONS
Preterm-born young adults exhibited a significantly impaired LV functional response to physical exercise.
This impairment was characterized by a lower exercise EF, which declined with increasing exercise intensity, as well as a reduced submaximal COR.
Resting echocardiography showed a significant relationship between birth history and LV structure and function that was consistent with our previous CMR Huckstep et al.