Diastolic Dysfunction Contributes to Impaired Cardiorespiratory Fitness in Patients with Lung Cancer and Reduced Lung Function Following Chest Radiation

Cardiorespiratory fitness (CRF) is a robust and independent predictor of cardiovascular health and overall mortality. Patients with lung cancer often have chronic lung disease, contributing to impaired CRF. Radiation to the heart during lung cancer treatment may further reduce CRF. The determinants of CRF in this population are not well understood. We prospectively evaluated 12 patients with lung cancer without known cardiovascular disease with reduced lung function receiving curative intent thoracic radiotherapy to determine whether cardiac diastolic function, as assessed by Doppler echocardiography and N-terminal pro-brain natriuretic peptide (NTproBNP) levels, correlate with CRF measured by peak oxygen consumption (VO2). Doppler-derived measures of diastolic function and serum NTproBNP levels inversely correlated with peak VO2. In a multivariate regression model, NTproBNP was the strongest independent variable associated with peak VO2. These results suggest that diastolic dysfunction further contributes to reduced CRF in patients with lung cancer who have received radiotherapy.


Introduction
Contemporary and sophisticated administration of thoracic radiotherapy has been effective in targeting tumor tissue while limiting exposure to the heart, yet studies have shown that symptoms of exercise intolerance seem to appear early after radiotherapy and contribute significantly to an impaired quality of life [1][2][3]. Cardiorespiratory fitness, reflected in peak oxygen consumption (VO 2 ), refers to the integrated ability of the cardiovascular and respiratory systems to supply oxygen to skeletal muscles during sustained physical activity. Lung cancer survivors consistently demonstrate poor CRF and studies have shown a strong inverse relationship between peak VO 2 and surgical outcomes, chemotherapy response, and survival [4][5][6].
Pulmonary function testing using spirometry to measure the forced expiratory volume in the first second (FEV 1 ) of a forced vital capacity (FVC) maneuver, is routinely measured in lung cancer patients in preparation for treatment and to identify high-risk patients requiring close follow-up. As expected, FEV 1 is often reduced in lung cancer patients. Reduced FEV 1 is strongly associated with mortality in these patients [7] and has been shown to play an integral role in predicting peak VO 2 [8].
Natriuretic peptides, such as N-terminal pro-brain natriuretic peptide (BNP, NTproBNP), have also been shown to correlate with peak VO 2 and are sensitive to change with interventions designed to improve CRF [9,10]. Several 1 3 studies have shown that in lung cancer patients, plasma levels of natriuretic peptides are elevated [11][12][13]. In particular, lung cancer patients with no known risk factors for elevated NTproBNP (≥ 125 pg/mL), were seven times more likely to have an elevated NTproBNP [12]. Moreover, Maeder et al. showed that natriuretic peptides were independently associated with a significantly impaired peak VO 2 in patients with lung disease [14]. However, NTproBNP is not routinely measured in lung cancer patients, and the additive role of NTproBNP in those with reduced FEV 1 remains unclear.
In the present study, we sought to determine if peak VO 2 is predicted by NTproBNP in lung cancer patients with reduced FEV 1 .

Methods
A prospective study was performed at Virginia Commonwealth University (VCU) enrolling patients with a history of chest cancers who had received thoracic radiotherapy with a resultant significant cardiac dose (≥ 5 Gy to ≥ 10% of the heart volume) with or without concurrent chemotherapy as part of curative treatment for malignancy. The main results of the study have been previously published [5]. We herein present data on a sub-analysis of patients with lung cancer following completion of radiotherapy. All patients underwent informed consent prior to enrollment. The study was approved by the VCU Massey Cancer Center Protocol Review and Institutional Review Board.
Participants were lung cancer survivors who were at least 18 years of age, able to perform treadmill exercise testing, had normal renal function (glomerular filtration rate > 60 mL/min/1.73 m 2 ) and were without a previously known diagnosis of cardiovascular disease or heart failure at the time of study enrollment. Subjects were evaluated with spirometry (including measurement of FEV 1 ), echocardiography (including measurement of left-ventricular ejection fraction [LVEF]; the ratio of early mitral inflow velocity to mitral annular early diastolic velocity averaged between the septal and lateral annulus [E/e′] as an estimate of left-ventricular filling pressure; the tricuspid annular plane systolic excursion (TAPSE) and systolic velocity at tissue Doppler (S') as a measure of right ventricular function), cardiopulmonary exercise testing (peak VO 2 ), and measurement of serum NTproBNP. Reduced FEV 1 was defined as < 80% of predicted with a FEV 1 /FVC ratio < 0.7. Only participants with reduced FEV 1 were included in this evaluation.
Radiation dose to the heart and lungs were evaluated separately and determined by dose-volume histograms from the pre-treatment planning computed tomography scans.
Data are reported as median and interquartile range (IQR) or number (%). Relationship between peak VO 2 and other variables was determined by Spearman's correlation coefficients or Mann-Whitney test for dichotomous variables. To investigate independent predictors of peak VO 2, we used a stepwise linear multivariate regression model including only identified clinical characteristics, spirometry, and echocardiography variables associated with a P < 0.05 at univariate analysis. Statistical analysis was conducted with SPSS 26.0 (IBM Corp, Armonk, NY, USA).

Results
We evaluated 15 patients that had received thoracic RT for the treatment of lung cancer ( Table 1) Peak VO 2 was not associated with age, sex, race, body mass index, current smoking status or pack-year history, cancer stage, history of cancer surgery, chemotherapy use (Yes/No), carboplatin dose (most common chemotherapeutic [53% use]), mean lung radiation dose, mean cardiac radiation dose, or total radiotherapy dose (all P > 0.10). Furthermore, we found no correlation between the LVEF, TAPSE, or S' and peak VO 2 (all P > 0.10).

Discussion
Cardiorespiratory fitness plays an important role in lung cancer morbidity, mortality and overall quality of life [2,4,7]. In this study, we report that patients with early stage and locally advanced lung cancer with reduced pulmonary function, but without a known pre-treatment history of cardiovascular disease or heart failure, demonstrate elevated NTproBNP serum levels that predict peak VO 2 following radiotherapy with and without chemotherapy. Our data suggest that biomarkers of cardiac function contribute to impaired CRF in patients with lung cancer in addition to pulmonary function, thus expanding our understanding of exercise intolerance in lung cancer. We can use this information to effectively screen lung cancer individuals with reduced FEV 1 and assess serum NTproBNP levels to allow for early identification of patients that could benefit from medical management (i.e., introduction of neuro-hormonal antagonists or exercise training interventions) or monitoring to minimize morbidity, improve overall quality of life, and potentially improve longevity.
The mechanism(s) driving this remain unclear and likely multifactorial, but cancer-related inflammation is believed to be a large contributor [15]. Right ventricular stress due to pulmonary pathology may also play a role.
We acknowledge that this sub-analysis has several limitations. First, this cohort included a small sample size. Second, we did not have pre-treatment (baseline) NTproBNP values for comparison, which would allow for direct comparison before and after treatment. Third, the diffusion capacity of the lungs for carbon monoxide was not measured in these patients, which may help elucidate key cardiac and pulmonary contributions to CRF in this population.

Conclusion
In stable patients with early and locally advanced lung cancer and reduced FEV 1 , diastolic dysfunction contributes to impaired CRF and serum NTproBNP levels independently predict peak VO 2 . This emphasizes the contribution of cardiac function to CRF of these patients and proposes NTproBNP as a marker for patient prognostication and possible therapeutic intervention.