Pulmonary vascular distensibility (α) is a marker of the ability of the pulmonary vasculature to dilate in response to increases in cardiac output, which protects the right ventricle from excessive increases in afterload. α measured with exercise predicts clinical outcomes in pulmonary hypertension (PH) and heart failure. In this study, we aim to determine if α measured with a passive leg raise (PLR) maneuver is comparable to α with exercise. Invasive cardiopulmonary exercise testing (iCPET) was performed with hemodynamics recorded at three stages: rest, PLR and peak exercise. Four hemodynamic phenotypes were identified (2019 ECS guidelines): pulmonary arterial hypertension (PAH) (n = 10), isolated post-capillary (Ipc-PH) (n = 18), combined pre-/post-capillary PH (Cpc-PH) (n = 15), and Control (no significant PH at rest and exercise) (n = 7). Measurements of mean pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac output at each stage were used to calculate α. There was no statistical difference between α-exercise and α-PLR (0.87 ± 0.68 and 0.78 ± 0.47% per mmHg, respectively). The peak exercise- and PLR-based calculations of α among the four hemodynamic groups were: Ipc-PH = Ex: 0.94 ± 0.30, PLR: 1.00 ± 0.27% per mmHg; Cpc-PH = Ex: 0.51 ± 0.15, PLR: 0.47 ± 0.18% per mmHg; PAH = Ex: 0.39 ± 0.23, PLR: 0.34 ± 0.18% per mmHg; and the Control group: Ex: 2.13 ± 0.91, PLR: 1.45 ± 0.49% per mmHg. Patients with α ≥ 0.7% per mmHg had reduced cardiovascular death and hospital admissions at 12-month follow-up. In conclusion, α-PLR is feasible and may be equally predictive of clinical outcomes as α-exercise in patients who are unable to exercise or in programs lacking iCPET facilities.

Pulmonary Hypertension (PH) is a challenging cardiopulmonary disease diagnosed when the mean pulmonary artery pressure (mPAP) is greater than 20 mmHg. Unfortunately, mPAP can only be measured through invasive right heart catheterization (RHC) motivating the development of novel non-invasive estimates. Pulmonary hypertension patients (n = 7) and control subjects (n = 8) had 2D phase contrast (PC) MRI of the main pulmonary artery during rest and moderate exercise. A novel method utilizing arterial mechanics was used to estimate mPAP and other pulmonary hemodynamics measures from the 2D PC images. mPAP estimated from MRI was greater in the PH group than the control group at both rest (24 ± 10 vs 12 ± 5 mmHg) and exercise (40 ± 8 vs 17 ± 9 mmHg). Area under the curve (AUC) calculated from receiver operator curve (ROC) analysis showed MRI estimated mPAP had excellent diagnostic ability to diagnose PH patients vs control subjects at rest and exercise (rest AUC = 0.91 [0.76 - 1.0], exercise AUC = 0.96 [0.88 - 1.0]). These are promising proof-of-concept results that pulmonary hemodynamics could be non-invasively estimated from an MRI and arterial mechanics approach. Future studies to determine the clinical utility of this method are needed.

A 48-year-old woman who had been receiving long-term interferon-β for 8 years for multiple sclerosis developed drug-induced World Health Organization group I pulmonary arterial hypertension. Triple therapy for pulmonary arterial hypertension and suspension of interferon-β led to improvement from a high-risk to low-risk state and improvement in exercise hemodynamics, including vascular distensibility, and right ventricle-pulmonary artery coupling. (Level of Difficulty: Advanced.).

Background

Among subjects with exercise intolerance and suspected early-stage pulmonary hypertension (PH), early identification of pulmonary vascular disease (PVD) with noninvasive methods is essential for prompt PH management.

Hypothesis

Rest gas exchange parameters (minute ventilation to carbon dioxide production ratio: V_E /VCO₂ and end-tidal carbon dioxide: ETCO₂ ) can identify PVD in early-stage PH.

Methods

We conducted a retrospective review of 55 subjects with early-stage PH (per echocardiogram), undergoing invasive exercise hemodynamics with cardiopulmonary exercise test to distinguish exercise intolerance mechanisms. Based on the rest and exercise hemodynamics, three distinct phenotypes were defined: (1) PVD, (2) pulmonary venous hypertension, and (3) noncardiac dyspnea (no rest or exercise PH). For all tests, *p < .05 was considered statistically significant.

Results

The mean age was 63.3 ± 13.4 years (53% female). In the overall cohort, higher rest V_E /VCO₂ and lower rest ETCO₂ (mm Hg) correlated with high rest and exercise pulmonary vascular resistance (PVR) (r ~ 0.5-0.6*). On receiver-operating characteristic analysis to predict PVD (vs. non-PVD) subjects with noninvasive metrics, area under the curve for pulmonary artery systolic pressure (echocardiogram) = 0.53, rest V_E /VCO₂  = 0.70* and ETCO₂  = 0.73*. Based on this, optimal thresholds of rest V_E /VCO₂  > 40 mm Hg and rest ETCO₂  < 30 mm Hg were applied to the overall cohort. Subjects with both abnormal gas exchange parameters (n = 12, vs. both normal parameters, n = 19) had an exercise PVR 5.2 ± 2.6* (vs. 1.9 ± 1.2), mPAP/CO slope with exercise 10.2 ± 6.0* (vs. 2.9 ± 2.0), and none included subjects from the noncardiac dyspnea group.

Conclusions

In a broad cohort of subjects with suspected early-stage PH, referred for invasive exercise testing to distinguish mechanisms of exercise intolerance, rest gas exchange parameters (V_E /VCO₂  > 40 mm Hg and ETCO₂  < 30 mm Hg) identify PVD.

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 (Z_C) 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.

Background

Right ventricular (RV) dilation has been used to predict adverse outcomes in acute pulmonary conditions. It has been used to categorize the severity of novel coronavirus infection (COVID-19) infection. Our study aimed to use chest CT-angiogram (CTA) to assess if increased RV dilation, quantified as an increased RV:LV (left ventricle) ratio, is associated with adverse outcomes in the COVID-19 infection, and if it occurs out of proportion to lung parenchymal disease.

Results

We reviewed clinical, laboratory, and chest CTA findings in COVID-19 patients (n = 100), and two control groups: normal subjects (n = 10) and subjects with organizing pneumonia (n = 10). On a chest CTA, we measured basal dimensions of the RV and LV in a focused 4-chamber view, and dimensions of pulmonary artery (PA) and aorta (AO) at the PA bifurcation level. Among the COVID-19 cohort, a higher RV:LV ratio was correlated with adverse outcomes, defined as ICU admission, intubation, or death. In patients with adverse outcomes, the RV:LV ratio was 1.06 ± 0.10, versus 0.95 ± 0.15 in patients without adverse outcomes. Among the adverse outcomes group, compared to the control subjects with organizing pneumonia, the lung parenchymal damage was lower (22.6 ± 9.0 vs. 32.7 ± 6.6), yet the RV:LV ratio was higher (1.06 ± 0.14 vs. 0.89 ± 0.07). In ROC analysis, RV:LV ratio had an AUC = 0.707 with an optimal cutoff of RV:LV ≥ 1.1 as a predictor of adverse outcomes. In a validation cohort (n = 25), an RV:LV ≥ 1.1 as a cutoff predicted adverse outcomes with an odds ratio of 76:1.

Conclusions

In COVID-19 patients, RV:LV ratio ≥ 1.1 on CTA chest is correlated with adverse outcomes. RV dilation in COVID-19 is out of proportion to parenchymal lung damage, pointing toward a vascular and/or thrombotic injury in the lungs.