Non-invasive pressure-volume loops show increased left ventricular contractility and arterial elastance in adolescents born very preterm, with an additive effect of fetal growth restriction

Background: Very preterm birth and fetal growth restriction (FGR) have both been linked to future cardiovascular disease. However, low birthweight is commonly used as a surrogate marker for FGR, leading to inclusion of those born small for other reasons such as being constitutionally small. Further, improved perinatal care has decreased cardiovascular effects, and clinical routine measurements of cardiac function are relatively normalized. Non-invasive pressure-volume loops can potentially show more subtle changes using hemodynamic parameters that are not previously measured in these populations.

The aim of this study was therefore to investigate whether very preterm birth or FGR is the main culprit for future cardiovascular disease, or if FGR has an additive effect to that of very preterm birth.

Methods: Adolescents born very preterm (< 30 gestational weeks) with verified FGR, defined as birthweight < 2 SD and pathological placental flow by Doppler ultrasound (preterm FGR), were compared to two control groups. First, those born very preterm at the same gestational age, but with appropriate birthweight for their age (preterm AGA), and those born at term (term). Non-invasive pressure-volume loops were calculated using brachial blood pressure and left ventricular volumes from cardiac magnetic resonance cine images. Values are median [interquartile range]. Groups were compared using Kruskal-Wallis with Dunn’s test for multiple comparisons and Jonckheere-Terpstra for trend analysis. P< 0.05 was considered to show statistically significant differences.

Results: Table 1 shows participants’ characteristics and clinical routine measurements of cardiac function. Preterm FGR had compared with term smaller indexed end-diastolic (80 vs 91 ml/m²) and end-systolic (36 vs 43 ml/m²) volumes. There was also a decreasing trend in heart rate from preterm FGR to preterm AGA to term (78 vs 73 vs 66 bpm; p=0.03).

Figure 1 shows contractility (E_max) and arterial elastance (E_a). Preterm FGR showed higher values compared to term for both contractility (1.58 [1.36–1.93] vs 1.25 [1.13–1.35] mmHg/ml; p=0.01) and for arterial elastance (1.44 [1.10–1.70) vs 1.16 (0.96–1.35) mmHg/ml; p=0.03). Contractility also showed a decreasing trend from preterm FGR to preterm AGA to term (1.58 vs 1.46 vs 1.25 mmHg/ml; p=0.002).

Conclusion: Smaller cardiac volumes are expected in adolescents after very preterm birth. The increased contractility shown for those born very preterm, with an additive effect of FGR, suggests they compensate the small hearts with increased contractility. This may in turn lead to a lesser ability to cope with exercise, which may be linked to the future cardiovascular disease found in other studies. Increased contractility and arterial elastance may possibly be early indicators of future cardiovascular disease after very preterm birth and FGR, even in those with normal cardiac function as measured by clinical routine measurements.

Characteristics.

	Preterm FGR	Preterm AGA	Term
Sex (boys)	6 (60%)	6 (60%)	5 (50%)
Age (year)	15 (14 – 16)	15 (13 – 16)	15 (13 – 16)
Height (cm)	160 (150 – 180)	171.5 (157 – 182.5)	175.5 (159.5 – 189)
Weight (kg)	48 (38 - 90)	57 (39 – 74)	57.5 (44 – 89)
BSA	1.44 (1.26 – 2.12)	1.66 (1.33 – 1.94)	1.68 (1.40 – 2.16)
SBP (mmHg)	105.8 (101–122.5)	100.3 (93.5 – 117)	104.5 (89 – 129.5)
DBP (mmHg)	56.5 (43.5 – 68.5)	53 (45 – 58)	49.5 (44.5 – 80)
EF (%)	56.9 (50 – 61.3)	58.1 (53.1 – 61.7)	53.6 (45.5 – 61.8)
EDV (ml)	113.6 (73.6 – 174.9)	134.1 (94.7 – 176.5)	144.0 (94.5 – 214.8)
ESV (ml)	52.7 (32.3 – 76.6)	53.9 (43.4 – 73.8)	71.3 (44.6 – 99.9)
SV (ml)	66.9 (41.3 – 98.3)	76.1 (51.3 – 102.8)	81.5 (50.0 – 118.0)
Heart rate (BPM)	80.5 (64 – 94)	74.5 (65 – 85)	66.5 (52 – 81)
Cardiac Output (L/min)	5.7 (3.7 – 7.9)	6.0 (4.1 – 8.0)	5.4 (3.6 – 9.3)
Cardiac index (L/min/m2)	3.8 (2.6 – 4.6)	3.4 (2.7 – 4.5)	3.0 (2.6 – 4.6)

Figure 1. Contractility and arterial elastance based on non-invasive pressure-volume loops in adolescence after very preterm birth due to fetal growth restriction (Preterm FGR), very preterm birth with appropriate birthweight for gestational age (Preterm AGA) and full-term healthy controls (Term). Contractility (left) was higher after very preterm birth due to FGR than in the full-term controls (1.58 [1.36–1.93] vs 1.25 [1.13–1.35] mmHg/ml). Contractility also showed a decreasing trend from very preterm birth due to FGR to very preterm birth AGA to full-term controls by the Jonckheere-Terpstra trend test (1.58 vs 1.46 vs 1.25 mmHg/ml; p = 0.002). Arterial elastance (right) was higher after very preterm birth due to FGR than in the full-term controls (1.58 [1.36–1.93] vs 1.25 [1.13–1.35] mmHg/ml). Lines represent median values.