Impaired Right Ventricular–Vascular Coupling in Young Adults Born Preterm

To the Editor:

The improved survival of extremely preterm infants into adulthood has increased recognition of impaired right ventricular (RV) performance and evidence of pulmonary vascular disease (PVD) arising beyond the neonatal period. Because the efficiency of the right ventricle depends on proper hemodynamic coupling with the typically compliant pulmonary arteries (PAs), which constitutes its afterload, a comprehensive evaluation of RV–PA coupling is central in the characterization of cardiopulmonary function (1). Recent work from our group demonstrated that prematurity leads to RV dysfunction and early evidence of PVD in young adulthood, but little is known regarding the long-term impact on RV–PA coupling (2). This coupling interaction was not available to report in our original study or a previously reported abstract (2, 3). We hypothesize that young adults born preterm have subclinical RV dysfunction with impaired RV–PA coupling.

We analyzed prospectively acquired data from our original study (2), obtained from adults who were born premature (n = 10, five male; current age 26.9 ± 0.3 yr; gestational age 28.6 ± 0.9 wk) and were recruited from the Newborn Lung Project, which includes a cohort of infants who were born in Wisconsin and Iowa between 1988 and 1991 and were longitudinally followed. Control subjects were born at term (n = 9, seven male; current age 25.8 ± 0.3 yr; gestational age 40.2 ± 0.2 wk) and recruited from the general population. The Institutional Review Board of the University of Wisconsin–Madison School of Medicine and Public Health approved all procedures. Informed consent was obtained from all subjects.

RV–PA coupling can be calculated as the ratio of end-systolic elastance (Ees, a measure of contractility) to effective arterial elastance (Ea, a measure of RV afterload). In this study, RV and PA pressure traces were obtained using two 3.5F high-fidelity, solid-state pressure sensor catheters (Mikro-Cath; Millar) at a sampling rate of 1 kHz. Cardiac magnetic resonance (CMR) images were acquired on a clinical 3T scanner (M750; GE Healthcare). ECG-gated, balanced, steady-state, free-precession images through the entire heart and two-dimensional phase-contrast images of the main PA (MPA) and aorta (Ao) were acquired. Images were manually contoured using Segment software (Medviso) to measure RV volumes and the relative area change of the MPA and Ao, calculated as [$\frac{\mathrm{M}\mathrm{a}\mathrm{x}\mathrm{i}\mathrm{m}\mathrm{a}\mathrm{l} \mathrm{a}\mathrm{r}\mathrm{e}\mathrm{a}-\mathrm{M}\mathrm{i}\mathrm{n}\mathrm{i}\mathrm{m}\mathrm{a}\mathrm{l} \mathrm{a}\mathrm{r}\mathrm{e}\mathrm{a}}{\mathrm{M}\mathrm{a}\mathrm{x}\mathrm{i}\mathrm{m}\mathrm{a}\mathrm{l} \mathrm{a}\mathrm{r}\mathrm{e}\mathrm{a}}$]. The ventricular stroke volume (SV) calculated as end-diastolic volume − end-systolic volume (ESV) was comparable to the SV derived from the MPA and Ao flow [$\frac{\stackrel{.}{\mathrm{Q}}}{\mathrm{H}\mathrm{e}\mathrm{a}\mathrm{r}\mathrm{t} \mathrm{R}\mathrm{a}\mathrm{t}\mathrm{e}}$].

The elastance relationship was calculated using the single-beat method from right heart catheterization, with Ees and Ea estimated as [$\frac{\mathrm{P}\mathrm{i}\mathrm{s}\mathrm{o}-\mathrm{P}\mathrm{e}\mathrm{s}}{\mathrm{S}\mathrm{V}}$] and [$\frac{\mathrm{P}\mathrm{e}\mathrm{s}}{\mathrm{S}\mathrm{V}}$], respectively (4, 5), where Pes is the end-systolic pressure. Piso represents the peak value of the interpolated sine wave from the two isovolumic portions of the second derivative of the RV pressure waveform (6). Because [$\frac{\mathrm{E}\mathrm{e}\mathrm{s}}{\mathrm{E}\mathrm{a}}$] can be simplified by omitting SV, RV–PA coupling becomes dependent on “pressure only” and can be calculated as [$\frac{\mathrm{P}\mathrm{i}\mathrm{s}\mathrm{o}}{\mathrm{P}\mathrm{e}\mathrm{s}}$−1]. Similarly, [$\frac{\mathrm{E}\mathrm{e}\mathrm{s}}{\mathrm{E}\mathrm{a}}$] can be simplified by omitting Pes and becomes dependent on “volume only” as calculated by [$\frac{\mathrm{S}\mathrm{V}}{\mathrm{E}\mathrm{S}\mathrm{V}}$] (4, 7). In addition, PA pressure and flow waveforms were used to determine the characteristic impedance, Z_C, a measure of proximal stiffness in the absence of wave reflections, and Z₀, the total pulmonary vascular resistance. Lastly, diastolic function was assessed via the relaxation time constant, τ_weiss.

All data are reported here as mean ± SE. Results were analyzed via two-sample t tests, and Grubbs’ test was performed to remove outliers. A P value of <0.05 was used to indicate statistical significance. All analyses were conducted with IBM SPSS Statistics software version 23.

Baseline characteristics are recorded in Table 1. Volumes calculated from the CMR images revealed no statistical differences in the body surface area indexed chamber volumes (end-diastolic volume index and ESV index) between the preterm and term-born subjects.

Table 1.

Baseline Characteristics

	Term-Born Young Adults	Preterm-Born Young Adults	P Value
Anthropometric data	n = 9	n = 10
Gestational age, wk	40.22 ± 0.14	28.60 ± 0.86	<0.001
Current age, yr	25.78 ± 0.26	26.90 ± 0.27	0.011
BSA, m2	1.90 ± 0.05	1.82 ± 0.07	>0.1
Sex, male, n (%)	7 (78%)	5 (50%)	>0.1
Structure and function	n = 6–9	n = 8–10
HR, bpm	73 ± 4	85 ± 4	0.089
MPA max area, cm2/m2	3.95 ± 0.13	4.37 ± 0.10	0.023
MPA RAC	0.36 ± 0.02	0.33 ± 0.02	>0.1
Ao max area, cm2/m2	3.68 ± 0.20	3.56 ± 0.22	>0.1
Ao RAC	0.22 ± 0.03	0.21 ± 0.02	>0.1
(MPA/Ao)/BSA, m−2	0.56 ± 0.03	0.71 ± 0.06	0.053
RV EDVi, ml/m2	85.54 ± 2.45	80.55 ± 2.23	>0.1
RV ESVi, ml/m2	32.55 ± 0.87	32.97 ± 0.98	>0.1
RV SVi, ml/m2	52.99 ± 2.20	47.58 ± 1.36	0.056
RV EF	0.62 ± 0.01	0.59 ± 0.01	0.041
LV EDVi, ml/m2	89.61 ± 3.51	82.39 ± 2.16	>0.1
LV ESVi, ml/m2	33.95 ± 1.35	32.53 ± 1.03	>0.1
LV SVi, ml/m2	55.66 ± 2.65	49.86 ± 1.29	0.075
LV EF	0.62 ± 0.01	0.61 ± 0.01	>0.1
LV SV/ESV	1.65 ± 0.07	1.54 ± 0.03	>0.1
Cardiopulmonary hemodynamics	n = 5–9	n = 4–10
mPAP, mm Hg	14.0 ± 1.2	20.33 ± 1.3	0.003
Piso, mm Hg	29.3 ± 1.9	33.9 ± 4.5	>0.1
Pes, mm Hg	11.2 ± 1.6	17.9 ± 1.9	0.030
Ea, mm Hg/ml	0.11 ± 0.02	0.20 ± 0.02	0.035
Ees, mm Hg/ml	0.18 ± 0.02	0.16 ± 0.04	>0.1
ZC, mm Hg ⋅ s/ml	1.22 ± 0.35	1.07 ± 0.27	>0.1
Z0, mm Hg ⋅ s/ml	1.97 ± 0.25	2.96 ± 0.21	0.014
τweiss, ms	27.46 ± 2.76	42.25 ± 6.05	0.085

Definition of abbreviations: Ao = aorta; BSA = body surface area; Ea = effective arterial elastance; EDVi = end-diastolic volume index (EDV/BSA); Ees = end-systolic elastance; EF = ejection fraction (SV/EDV); ESVi = end-systolic volume index (ESV/BSA); HR = heart rate; LV = left ventricle; MPA = main pulmonary artery; mPAP = mean pulmonary artery pressure; Pes = end-systolic pressure; Piso = isovolumetric pressure obtained from the single-beat method; RAC = relative area change; RV = right ventricle; SVi = stroke volume index (SV/BSA); τ_weiss = time constant of ventricular relaxation; Z_C = characteristic impedance; Z₀ = zero Hz impedance.

Data are shown as mean ± SE. Bold indicates P < 0.05.

Pressure waveform analysis revealed that preterm subjects had increased total pulmonary vascular resistance (Z₀) that contributed to increased RV afterload (0.11 ± 0.02 vs. 0.20 ± 0.02 mm Hg/ml; P = 0.035). This contributed to increased Pes (11.2 ± 1.6 vs. 17.9 ± 1.9 mm Hg; P = 0.030) and reduced RV ejection fraction (0.62 ± 0.01 vs. 0.59 ± 0.01; P = 0.041) and RV stroke volume index (52.99 ± 2.20 vs. 47.58 ± 1.36 ml/m²; P = 0.056), which could indicate the beginning stages of RV systolic dysfunction.

Analysis of the CMR phase-contrast images revealed increased PA dilation in preterm subjects, whereas the Ao area was comparable between the preterm and term-born subjects. However, no difference in the stiffness of the PA was measured between the preterm and term-born subjects, as estimated noninvasively via the relative area change and invasively by the characteristic impedance, Z_C.

Preterm subjects had an increased RV relaxation time constant, τ_weiss (27.46 ± 2.76 vs. 42.25 ± 6.05 ms; P = 0.085), suggesting reduced RV diastolic function. Lastly, no compensatory changes in RV contractility were observed in preterm subjects. Maintained contractility with increased RV afterload led to reduced RV–PA coupling as calculated by both the pressure- and volume-only methods (Figure 1). Good agreement was found between the two methods (Pearson coefficient R² = 0.78; P < 0.001).

Figure 1.

Right ventricular–pulmonary arterial coupling as estimated by a volume-only method (left) and a pressure-only method (right). Numbers within the symbols are used to denote specific patients to compare the two methods. Optimal mechanical coupling occurs when the end-systolic elastance (Ees) to effective arterial elastance (Ea) ratio is equal to 1, and optimal energy transfer occurs when Ees/Ea falls between 1.5 and 2.0 (9). ESV = end-systolic volume; Pes = end-systolic pressure; Piso = isovolumetric pressure obtained from the single-beat method; SV = stroke volume.

Although the preterm subjects in this study were healthy, active individuals, they demonstrated early signs of RV systolic and diastolic dysfunction and decreased RV–PA coupling. Several preterm subjects also presented with PA pressures consistent with pulmonary hypertension (2). This study was not designed to address the causation or mechanistic progression of reduced RV–PA coupling; however, we previously demonstrated mitochondrial DNA damage and dysregulated biogenesis in a rat model of prematurity-related lung disease (8). These animals also developed RV–PA uncoupling in a setting of modest pulmonary hypertension, which we proposed represents an intrinsic RV insult of prematurity. Future studies are needed to test these mechanisms.

The results of this study should be interpreted within the framework of its inherent limitations, primarily the small sample size and the asynchronous acquisition of RV pressures and volumes. The single-beat method was not validated against the gold-standard, multibeat method with a preload reduction in subjects with PVD; however, the benefits associated with the single-beat method as a measure of RV–PA coupling have been well described (4).

In summary, otherwise healthy, young adults who were born preterm were found to have high-resistance/low-compliance pulmonary vascular beds with attenuated RV adaptation in the face of increased vascular load. This resulted in impaired RV–PA coupling, as demonstrated by two different methods. These findings add to the growing evidence that preterm birth has profound lifelong consequences that warrant further study.