Heart rate recovery in 1 minute after the 6minute walk test predicts adverse outcomes in pulmonary arterial hypertension
Rezende CF, Mancuzo EV, Corrêa RA. Heart rate recovery in 1 minute after the 6-minute walk test predicts adverse outcomes in pulmonary arterial hypertension. PLoS One. 2022 May 27;17(5):e0268839. doi: 10.1371/journal.pone.0268839. PMID: 35622825; PMCID: PMC9140226.Link to Original Article: https://pubmed.ncbi.nlm.nih.gov/35622825/
Key Points
1. The study aimed to determine the cutoff value and accuracy for abnormal heart rate recovery in 1 minute (HRR1) after the 6-minute walk test (6MWT) and investigate its association with adverse outcomes in patients with pulmonary arterial hypertension (PAH).
2. A prospective cohort study of 102 patients with confirmed PAH found that an HRR1 value of less than 18 beats may be a reliable indicator of poor prognosis, with a lower event-free time compared to those with HRR1 of 18 beats or more.
3. The study established a cutoff value of 17 beats for HRR1 to discriminate clinical worsening in PAH patients, with an area under the curve (AUC) of 0.704 and a sensitivity of 0.83 and specificity of 0.56 for predicting adverse outcomes.
4. Patients with HRR1 <18 beats at baseline had increased risk of all-cause mortality, hospitalization, and disease progression, independent of other 6MWT variables.
5. Reduced HRR1 was associated with worse World Health Organization functional class, oxygen use, and decreased exercise capacity, indicating its potential as an independent biomarker of PAH severity and prognosis.
6. The study highlights the potential of HRR1 as a non-invasive marker of autonomic dysfunction in PAH, suggesting its usefulness in risk stratification and the need for further investigation in prospective studies.
Introduction
The introduction of the research paper highlights the significance of predicting adverse outcomes in patients with pulmonary arterial hypertension (PAH) and the existing methods for prognosis assessment, including risk scores and the 6-minute walk test (6MWT). It points out the correlation between walking distance (6MWD) and prognosis, emphasizing the potential of heart rate recovery in 1 minute (HRR1) as a predictive tool for PAH prognosis due to its indication of ongoing autonomic dysfunction. The relevance of reduced HRR1 in other conditions such as congestive heart failure and chronic obstructive pulmonary disease is noted, along with the lack of an established cut-off value for HRR1. The main objective of the pilot study is to identify a specific cut-off value of HRR1 associated with adverse outcomes and to analyze factors contributing to reduced HRR1 in a selected sample of PAH patients. The introduction sets the stage for the importance of exploring HRR1 as a potential prognostic indicator in PAH and outlines the specific aims of the study, thereby providing a comprehensive rationale for the research.
Methods
Study design
The study was a prospective observational cohort that included participants with pulmonary arterial hypertension (PAH) recruited from the Pulmonary Circulation Unit of Hospital das Clínicas of the Federal University of Minas Gerais in Belo Horizonte, Brazil, between September 2004 and April 2020, and they were followed up until April 2021 or death. Before the initiation of PAH therapy, clinical and laboratory assessments, N-terminal pro-brain-type natriuretic peptide (NT-proBNP) levels, echocardiography, right heart catheterization (RHC) variables, and the Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) risk score were recorded. The study involved follow-up visits every 3 to 6 months, during which updates on participants' medical status were documented using a standardized form. This design allowed for the comprehensive collection of data on the participants' clinical characteristics, disease severity, and treatment, and facilitated the assessment of the potential use of heart rate recovery in 1 minute (HRR1) as a predictor of adverse outcomes in PAH patients.
Study population
The study population consisted of patients who were 18 years or older and had a newly confirmed diagnosis of idiopathic pulmonary arterial hypertension (IPAH) or were classified into various PAH subgroups such as schistosomiasis (SchPAH), congenital heart disease (CHDPAH), connective tissue disease (CTDPAH), portopulmonary hypertension (PoPH), and HIV infection (HIVPAH), and were able to perform the 6-minute walk test (6MWT). Patients using β-blockers or PAH-specific therapy before the 6MWT and right heart catheterization at the baseline test, as well as those with other causes of pulmonary hypertension, pregnancy, and prevalent cases were excluded from the study. The research was approved by an ethics committee and conducted in accordance with the Declaration of Helsinki. The confidentiality of the information obtained from the participants was maintained, and the reports and results of the study were presented without any form of individual identification. All participants provided informed consent for their involvement in the study.
Six-minute walk test
The study conducted the 6-minute walk test (6MWT) on patients with confirmed pulmonary arterial hypertension (PAH) before beginning specific treatment, in line with international standards. The test was performed in a 30-meter corridor, and saturation by pulse oximetry (SpO2), heart rate (HR), respiratory rate (RR), and Borg dyspnea score were recorded before and after the test. Additionally, heart rate recovery in 1 minute (HRR1) and the 6-minute walk distance (6MWD) in both absolute and percentage of the predicted value were measured using a reference equation for the Brazilian population. Supplementary oxygen was provided as needed during the test, and a decrease in saturation by 4% or more was considered significant. This comprehensive assessment allowed for the evaluation of the patients' exercise capacity, oxygen saturation, heart rate response, and dyspnea levels during physical exertion. These measures are crucial for understanding the functional status and prognosis of PAH patients and can provide valuable insights into their disease progression and treatment outcomes.
Outcomes
The study identified the outcome as decrease of ≥15% in 6MWD from the baseline and worsening of World health Organization functional class (WHO-FC) or need for additional PAH therapy.
Statistical analysis
The researchers used the statistical software SPSS, version 23.0, for data analysis. They presented results as frequency and proportions, mean (SD), or median (IQ range) as appropriate. To assess the association between HRR1 and other variables, they used independent t-tests or Mann-Whitney tests for continuous variables and Pearson chi-squared tests or Fisher exact tests for categorical variables. The receiver operator characteristic (ROC) curve was used to select the HRR1 admission value with the best accuracy in predicting outcomes, and the internal validation of the model was examined using bootstrap with replacement sampling with 1000 bootstrap samples. A p-value of <0.05 was considered significant.
The researchers used Kaplan-Meier curves and time-dependent ROC curves to assess the prognostic value of HRR1 at admission for PAH patients. They tested statistical significance using the log-rank method. Overall, the statistical analysis involved various tests to assess associations, select the best predictive value of HRR1, and internally validate the model. The researchers also used Kaplan-Meier and time-dependent ROC curves to evaluate the prognostic value of HRR1 at admission for PAH patients and determine its statistical significance.
Results
Baseline characteristics at time of diagnosis
The study followed 102 out of 109 patients diagnosed with pulmonary arterial hypertension (PAH) for a median of 2.42 years. The patients had a mean age of 48 years, with 68.6% being women and mostly in functional class (FC) II (41.2%) and III (44.1%). The prevailing etiologies were SchPAH (29.4%), IPAH (23.5%), CHDPAH (20.6%), CTDPAH (15.7%), PoPH (6.9%), and HIVPAH (3.9%). The median baseline heart rate recovery in 1 minute (HRR1) was 18 beats, with 50 patients having <18 beats and 52 patients having ≥18 beats, and these findings were consistent across the subgroups. Initially, 97% of patients received monotherapy for PAH, which was later modified to combined therapy in 61% of patients during follow-up.
Patients with HRR1 ≥18 beats exhibited better World Health Organization functional class, PAH risk stratification, % predicted diffusion capacity of carbon monoxide, and 6-minute walk distance, along with a higher frequency of oxygen use and 6-minute walk test interruption compared to those with HRR1 <18 beats. However, there were no significant differences between the two HRR1 groups in echocardiography and hemodynamics parameters.
Accuracy of HRR1 in predicting clinical worsening
The research examined the accuracy of heart rate recovery in 1 minute (HRR1) in predicting clinical worsening in patients with pulmonary arterial hypertension. The study found that HRR1 <18 beats had a regular discriminatory power, with an area under the curve (AUC) of 0.704 (95%CI: 0.584-0.824). The HRR1 value with the best discriminatory power for predicting the outcome was 17 beats, with a sensitivity of 0.83, specificity of 0.56, negative predictive value (NPV) of 1.00, and positive predictive value (PPV) of 0.009. The internal validation model by bootstrap showed an AUC of 0.676 (95%CI: 0.566-0.786) with a cut-off value of 17 beats, providing a sensitivity of 0.66, specificity of 0.78, NPV of 1.00, and PPV of 0.002. Additionally, the maximum accuracy for the combined outcome was achieved at the 7-year onwards follow-up, with an AUC of 0.711 (95%CI: 0.596-0.844). These findings suggest that HRR1 <18 beats and specifically 17 beats may serve as valuable indicators for predicting clinical worsening in patients with pulmonary arterial hypertension, providing important insights for the potential use of HRR1 as a predictive tool in this patient population.
Survival analysis
In the survival analysis section of the study, the researchers found that patients with a heart rate recovery in 1 minute (HRR1) of less than 18 beats at baseline had a higher risk of experiencing adverse outcomes compared to those with HRR1 of 18 beats or more. This association was found to be independent of other variables related to the six-minute walk test (6MWT). The median event-free time for patients with HRR1 <18 beats was 2.17. The distribution of outcomes observed during the follow-up period included disease progression (55%), hospitalization (20%), death (1%), and 24% of patients had no adverse events. The primary causes of death in the study population were right ventricular failure (n = 25), sepsis (n = 7), liver failure (n = 4), pulmonary embolism (n = 1), and pulmonary artery dissection (n = 1). These findings suggest that HRR1 <18 beats at baseline is associated with an increased risk of adverse outcomes in patients with pulmonary arterial hypertension, with the most common cause of death being right ventricular failure.
Discussion
The study investigated the use of heart rate recovery in 1 minute (HRR1) as a potential tool for predicting adverse outcomes in patients with pulmonary arterial hypertension (PAH). The findings revealed that an HRR1 of <18 beats at baseline had a high negative predictive value for predicting all-cause mortality, hospitalization, and disease progression in the participants. It was noted that HRR1 is an indicator of autonomic dysfunction, with a value <18 beats associated with a worse prognosis. The reduced cardiac output due to right ventricle dysfunction in patients with more severe disease, along with sympathetic hyperactivity and reduced parasympathetic activity, were suggested as potential mechanisms involved in this response.
Previous studies have associated HRR1 with clinical outcomes in PAH, and the current study reaffirmed HRR1 as an independent biomarker of PAH severity. Reduced HRR1 was associated with worse functional classification, gas exchange, PAH risk stratification, and decreased exercise capacity. However, the study was limited by its single-center design and the prevalence of a specific type of PAH, which may impact generalizability. The study concluded that a delay in HRR1 of <18 beats predicts the risk of clinical outcomes in PAH, irrespective of the initial 6-minute walk distance (6MWD). The authors suggested that further investigation of this variable in stratifying risk in PAH patients is warranted in prospective studies.
