Corrado, Philip A.

Abstract Deep phenotyping of pulmonary hypertension (PH) with multimodal diagnostic exercise interventions can lead to early focused therapeutic interventions. Herein, we report methods to simultaneously assess pulmonary impedance, differential biventricular myocardial strain, and right ventricular:pulmonary arterial (RV:PA) uncoupling during exercise, which we pilot in subjects with suspected PH. As proof-of-concept, we show that four subjects with different diagnoses [pulmonary arterial hypertension (PAH); chronic thromboembolic disease (CTEPH); PH due to heart failure with preserved ejection fraction (PH-HFpEF); and noncardiac dyspnea (NCD)] have distinct patterns of response to exercise. RV:PA coupling assessment with exercise was highest-to-lowest in this order: PAH > CTEPH > PH-HFpEF > NCD. Input impedance (Z0) with exercise was highest in precapillary PH (PAH, CTEPH), followed by PH-HFpEF and NCD. Characteristic impedance (ZC) tended to decline with exercise, except for the PH-HFpEF subject (initial Zc increase at moderate workload with subsequent decrease at higher workload with augmentation in cardiac output). Differential myocardial strain was normal in PAH, CTEPH, and NCD subjects and lower in the PH-HFpEF subject in the interventricular septum. The combination of these metrics allowed novel insights into mechanisms of RV:PA uncoupling. For example, while the PH-HFpEF subject had hemodynamics comparable to the NCD subject at rest, with exercise coupling dropped precipitously, which can be attributed (by decreased myocardial strain of interventricular septum) to poor support from the left ventricle (LV). We conclude that this deep phenotyping approach may distinguish afterload sensitive vs. LV-dependent mechanisms of RV:PA uncoupling in PH, which may lead to novel therapeutically relevant insights.

Introduction: Individuals born premature have smaller ventricular chambers volumes and a reduced cardiac reserve during exercise. Epidemiologic studies demonstrate increased risk of developing heart failure by young adulthood, though whether this is due primarily to systolic or diastolic dysfunction remains unresolved. Hypothesis: We hypothesize that either systolic or diastolic function, quantified as intraventricular kinetic energy (KE) during systolic and diastolic phases, respectively, will be altered in both ventricles of young adults born premature. Methods: A total of 56 young adults participated in this observational cardiac MRI study: 35 subjects born moderately to extremely premature (birth weight <1500 g or gestational age ≤32 weeks), and 21 age-matched term-born subjects. Each subject underwent cardiac MRI, including cine cardiac structure/function assessment and four-dimensional flow-encoded MRI (4D flow MRI). Five 4D flow parameters, normalized by end diastolic volume (EDV) to control for heart size, were extracted from each ventricle’s KE-time curve: average KE/EDV, peak systolic KE/EDV, early diastolic (E-wave) KE/EDV, late diastolic (A-wave) KE/EDV, and the ratio of E-wave KE to A-wave KE. Results: Average KE/EDV and peak systolic KE/EDV were similar between term and preterm subjects. Preterm-born subjects had increased A-wave KE/EDV in the RV and decreased E/A KE ratio in both ventricles (Table 1), indicating subtle diastolic dysfunction. The E/A KE ratio was moderately correlated with stroke volume index in both ventricles (LV: R=0.37, P=0.005; RV: R=0.32, P=0.02). Conclusions: Our results suggest that diastolic dysfunction, along with reduced chamber size, contributes to the reduced stroke volume seen in individuals born premature. In addition, diastolic dysfunction may further limit cardiac functional reserve and increase early heart failure risk in this population.

We assessed the effect of right ventricular afterload reduction with sildenafil and heart rate reduction with metoprolol on cardiac hemodynamics and function in young adults born premature using 4D flow MRI. Metoprolol depressed cardiac function, whereas sildenafil improved cardiac function including right ventricular direct flow fraction by 4D flow, consistent with hemodynamic improvement. This suggests that the preterm heart is dependent on heart rate and sensitive to right ventricular afterload changes.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/behind-the-bench-episode-9 .