The effects of oxygenation on acute vasodilator challenge in pulmonary arterial hypertension.

Identification of long-term calcium channel blocker (CCB) responders with acute vasodilator challenge is critical in the evaluation of patients with pulmonary arterial hypertension. Currently there is no standardized approach for use of supplemental oxygen during acute vasodilator challenge. In this retrospective analysis of patients identified as acute vasoresponders, treated with CCBs, all patients had hemodynamic measurements in three steps: (1) at baseline; (2) with 100% fractional inspired oxygen; and (3) with 100% fractional inspired oxygen plus inhaled nitric oxide (iNO). Those meeting the definition of acute vasoresponsiveness only after first normalizing for the effects of oxygen in step 2 were labeled "iNO Responders." Those who met the definition of acute vasoresponsiveness from a combination of the effects of 100% FiO2 and iNO were labeled "oxygen responders." Survival, hospitalization for decompensated right heart failure, duration of CCB monotherapy, and functional data were collected. iNO responders, when compared to oxygen responders, had superior survival (100% vs. 50.1% 5-year survival, respectively), fewer hospitalizations for acute decompensated right heart failure (0% vs. 30.4% at 1 year, respectively), longer duration of CCB monotherapy (80% vs. 52% at 1 year, respectively), and superior 6-min walk distance. Current guidelines for acute vasodilator testing do not standardize oxygen coadministration with iNO. This study demonstrates that adjusting for the effects of supplemental oxygen before assessing for acute vasoresponsiveness identifies a cohort with superior functional status, tolerance of CCB monotherapy, and survival while on long-term CCB therapy.

Right ventricular performance during acute hypoxic exercise.

Acute hypoxia increases pulmonary arterial (PA) pressures, though its effect on right ventricular (RV) function is controversial. The objective of this study was to characterize exertional RV performance during acute hypoxia. Ten healthy participants (34 ± 10 years, 7 males) completed three visits: visits 1 and 2 included non-invasive normoxic (fraction of inspired oxygen ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) = 0.21) and isobaric hypoxic ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12) cardiopulmonary exercise testing (CPET) to determine normoxic/hypoxic maximal oxygen uptake ( V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ). Visit 3 involved invasive haemodynamic assessments where participants were randomized 1:1 to either Swan-Ganz or conductance catheterization to quantify RV performance via pressure-volume analysis. Arterial oxygen saturation was determined by blood gas analysis from radial arterial catheterization. During visit 3, participants completed invasive submaximal CPET testing at 50% normoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ and again at 50% hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12). Median (interquartile range) values for non-invasive V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ values during normoxic and hypoxic testing were 2.98 (2.43, 3.66) l/min and 1.84 (1.62, 2.25) l/min, respectively (P < 0.0001). Mean PA pressure increased significantly when transitioning from rest to submaximal exercise during normoxic and hypoxic conditions (P = 0.0014). Metrics of RV contractility including preload recruitable stroke work, dP/dtmax , and end-systolic pressure increased significantly during the transition from rest to exercise under normoxic and hypoxic conditions. Ventricular-arterial coupling was maintained during normoxic exercise at 50% V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ . During submaximal exercise at 50% of hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ , ventricular-arterial coupling declined but remained within normal limits. In conclusion, resting and exertional RV functions are preserved in response to acute exposure to hypoxia at an F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12 and the associated increase in PA pressures. KEY POINTS: The healthy right ventricle augments contractility, lusitropy and energetics during periods of increased metabolic demand (e.g. exercise) in acute hypoxic conditions. During submaximal exercise, ventricular-arterial coupling decreases but remains within normal limits, ensuring that cardiac output and systemic perfusion are maintained. These data describe right ventricular physiological responses during submaximal exercise under conditions of acute hypoxia, such as occurs during exposure to high altitude and/or acute hypoxic respiratory failure.

Exercise Testing in the Risk Assessment of Pulmonary Hypertension.

TOPIC IMPORTANCE: Right ventricular dysfunction in pulmonary hypertension (PH) contributes to reduced exercise capacity, morbidity, and mortality. Exercise can unmask right ventricular dysfunction not apparent at rest, with negative implications for prognosis. REVIEW FINDINGS: Among patients with pulmonary vascular disease, right ventricular afterload may increase during exercise out of proportion to increases observed among healthy individuals. Right ventricular contractility must increase to match the demands of increased afterload to maintain ventricular-arterial coupling (the relationship between contractility and afterload) and ultimately cardiac output. Impaired right ventricular contractile reserve leads to ventricular-arterial uncoupling, preventing cardiac output from increasing during exercise and limiting exercise capacity. Abnormal pulmonary vascular response to exercise can signify early pulmonary vascular disease and is associated with increased mortality. Impaired right ventricular contractile reserve similarly predicts poor outcomes, including reduced exercise capacity and death. Exercise provocation can be used to assess pulmonary vascular response to exercise and right ventricular contractile reserve. Noninvasive techniques (including cardiopulmonary exercise testing, transthoracic echocardiography, and cardiac MRI) as well as invasive techniques (including right heart catheterization and pressure-volume analysis) may be applied selectively to the screening, diagnosis, and risk stratification of patients with suspected or established PH. Further research is required to determine the role of exercise stress testing in the management of pulmonary vascular disease. SUMMARY: This review describes the current understanding of clinical applications of exercise testing in the risk assessment of patients with suspected or established PH.

Tensions in Taxonomies: Current Understanding and Future Directions in the Pathobiologic Basis and Treatment of Group 1 and Group 3 Pulmonary Hypertension.

In the over 100 years since the recognition of pulmonary hypertension (PH), immense progress and significant achievements have been made with regard to understanding the pathophysiology of the disease and its treatment. These advances have been mostly in idiopathic pulmonary arterial hypertension (IPAH), which was classified as Group 1 Pulmonary Hypertension (PH) at the Second World Symposia on PH in 1998. However, the pathobiology of PH due to chronic lung disease, classified as Group 3 PH, remains poorly understood and its treatments thus remain limited. We review the history of the classification of the five groups of PH and aim to provide a state-of-the-art review of the understanding of the pathogenesis of Group 1 PH and Group 3 PH including insights gained from novel high-throughput omics technologies that have revealed heterogeneities within these categories as well as similarities between them. Leveraging the substantial gains made in understanding the genomics, epigenomics, proteomics, and metabolomics of PAH to understand the full spectrum of the complex, heterogeneous disease of PH is needed. Multimodal omics data as well as supervised and unbiased machine learning approaches after careful consideration of the powerful advantages as well as of the limitations and pitfalls of these technologies could lead to earlier diagnosis, more precise risk stratification, better predictions of disease response, new sub-phenotype groupings within types of PH, and identification of shared pathways between PAH and other types of PH that could lead to new treatment targets. © 2023 American Physiological Society. Compr Physiol 13:4295-4319, 2023.

A 58-Year-Old Woman With a History of Cardiac Myxoma Presents With Pulmonary Nodules.

CASE PRESENTATION: A 58-year-old woman presented to a pulmonology clinic for evaluation of bilateral pulmonary nodules. Two years previously, she had presented with atrioventricular nodal reentrant tachycardia. During evaluation for her tachyarrhythmia, transthoracic echocardiogram (TTE) revealed a large, homogenous, highly mobile right atrial and ventricular mass. She underwent electrophysiologic ablation, tricuspid valve annular ring replacement, and resection of the mass, which pathology confirmed to be a myxoma. Now, a recent abdomen and pelvis CT study obtained for history of nephrolithiasis incidentally noted bilateral lower lobe pulmonary nodules. Follow-up noncontrast chest CT confirmed bilateral peribronchovascular solid pulmonary nodules up to 8 mm in diameter throughout all lobes. The nodules appeared contiguous with the segmental and subsegmental bronchovascular bundles, and many occurred at branch points. There was no mediastinal or hilar lymphadenopathy. To evaluate the pulmonary nodules, she was referred to a pulmonology clinic. She reported only stable, nonlimiting dyspnea on exertion. She did not have a cough. She denied a history of fevers, weight loss, or night sweats. She had no rash or skin changes, visual changes, joint pain or swelling, or palpitations. She had no history of oropharyngeal or genital ulcerations. Social history was notable for a 40-pack-year smoking history, with quit date 2 years prior. She had no risk factors for TB exposure and no exposures to sandblasting, stone cutting, or other environmental risk factors for silicosis. Family history was negative for autoimmune conditions, sarcoidosis, and lymphoproliferative disorders.

Prognostic significance of functional capacity and exercise behavior in patients with metastatic non-small cell lung cancer.

BACKGROUND: To investigate the prognostic importance of functional capacity and exercise behavior in patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Using a prospective design, 118 consecutive participants with histologically confirmed metastatic (inoperable) NSCLC and Eastern Cooperative Oncology group (ECOG) 0-3 completed a six-minute walk test to assess functional capacity and questionnaire that assessed self-reported exercise behavior. Cox proportional models were used to estimate the risk of all-cause mortality according to six-minute walk distance (6MWD) (<358.5m, 358.5-450 m, ≥450 m) and exercise behavior (MET-hrswk(-1)) categories with adjustment for important covariates. RESULTS: Median follow-up was 26.6 months; 77 deaths were reported during this period. Functional capacity was an independent predictor of survival (P(trend)=0.003) and added incremental prognostic value beyond that provided by PS plus other traditional markers of prognosis (P(trend)=0.025). Compared with patients achieving a 6MWD <358.5m, the adjusted hazard ratio (HR) for all-cause mortality was 0.61 (95% CI, 0.34-1.07) for a 6MWD of 358.5-450 m, and 0.48 (95% CI, 0.24-0.93) for a 6MWD >450 m. In unadjusted analysis, there was a borderline significant effect of exercise behavior on survival (p=0.052). Median survival was 12.89 months (95% CI, 9.11-21.05 months) for those reporting <9MET-hrswk(-1) compared with 25.63 months (95% CI, 11.28 to ∞ months) for those reporting ≥9MET-hrswk(-1). CONCLUSIONS: Functional capacity is a strong independent predictor of survival in advanced NSCLC that adds to the prediction of survival beyond traditional risk factors. This parameter may improve risk stratification and prognostication in NSCLC.