Exercise-Induced Electrocardiography Changes in Pulmonary Arterial Hypertension.

Cardiopulmonary exercise testing (CPET) is an important tool in assessing the functional status of patients with pulmonary arterial hypertension (PAH). During CPET, continuous electrocardiography (ECG) is used as a marker of exercise-induced ischemia or arrhythmia. We hypothesize that ECG changes with exercise may be an early indicator of clinical worsening in PAH and could predict adverse outcomes. Clinical, hemodynamic, and CPET data of 155 children and young adult patients with PAH who underwent CPET between 2012 and 2019 in our pulmonary hypertension (PH) center were included in this retrospective analysis. ECGs were analyzed for ST depressions and T-wave inversions, along with coincident hemodynamic data. These data were correlated with adverse outcomes divided into 2 categories: severe worsening (death or receiving lung transplant) and mild to moderate worsening (PAH medication escalation, hospitalization, shunt creation, or listing for lung transplant). The median age was 19 years (range 7 to 40 years), 69% were female, and the average follow-up time was 5 years (range 1 to 8 years). A total of 63 patients (41%) had at least 1 adverse outcome. A total of 39 patients (25%) demonstrated significant ST-T-wave changes with exercise. Patients with ST-T-wave changes were 20% more likely to die or need lung transplant than those without. The multiple linear regression found that ST-T-wave changes were a predictor of elevated mean pulmonary arterial pressure (mPAP) found on catheterization (R = 0.489, p = 0.003), although not of pulmonary vascular resistance index (R = -0.112, p = 0.484). An mPAP of 55 mm Hg was the most sensitive and specific point in identifying when ST-T-wave changes with exercise begin to appear. In conclusion, ST-T-wave changes on exercise ECG are significantly associated with adverse outcomes in PH in a medium-term follow-up study, and the presence of ST-T-wave changes correlates with higher mPAP. These ECG changes with exercise may be used as early indicators of clinical worsening in PH and predictors of adverse outcomes.

Average Exercise Capacity in Men and Women >75 Years of Age Undergoing a Bruce Protocol Exercise Stress Test.

Exercise stress testing is routinely performed to evaluate suspected coronary artery disease in older adults. However, the available data to predict and compare relative exercise capacity in the general population were developed using predominantly younger, healthy cohorts with few or no women. This study aimed to describe the exercise capacity of patients older than 75 years who underwent a clinically indicated Bruce protocol exercise stress test. This was a retrospective, cross-sectional study of 2,041 consecutive patients older than 75 years who performed a Bruce protocol exercise stress echocardiogram that was terminated because of maximal effort without ischemia at Columbia University Medical Center between April 10, 2009, and July 30, 2020. The analytic sample included 2,041 exercise stress tests in 786 women (median [interquartile range] age 79 [77 to 81] years) and 1,255 men (median [interquartile range] age 79 [77 to 82] years). Cardiovascular risk factors and clinical coronary disease were common and more prevalent in men than women. The median exercise time for men aged 76 to 80 years was 7:22 (minutes:seconds) and for women was 6:00 and significantly decreased in both genders as age increased (p <0.001). The mean (SD) METs achieved for women and men were 6.5 (1.6) and 7.7 (1.7), respectively. Most women (85%) and men (95%) completed the first stage, whereas only 32% of women and 64% of men completed the second stage. It was uncommon for women (3%) or men (15%) to complete the third stage. Fewer than 1% of patients completed the fourth stage, and none completed the fifth stage. At all ages, women had a lower exercise capacity than men. These data allow physicians to compare the exercise capacity of older patients who underwent a Bruce protocol exercise stress test more accurately to a representative sample of similarly aged adults.

The Families Improving Health Together (FIT) Program: Initial evaluation of retention and research in a multispecialty clinic for children with obesity.

BACKGROUND: Obesity affects ∼17% of US children, with parallel increases in multiple comorbidities, especially among African-, Asian-, Hispanic-, and Native-Americans. Barriers to patient retention in pediatric obesity programs include lack of centralized care, and frequent subspecialty MD visits which conflict with patient school attendance and parental work attendance as well as with support service utilization. Lack of integration of multispecialty clinical care with interdisciplinary research is a major barrier to fuller exploration of the treatment, prevention, and understanding of obesity in childhood. OBJECTIVE: To test the hypothesis, a novel multispecialty/interdisciplinary clinical and research infrastructure with strong emphasis on a primary obesity care physician for children with early-onset (<9 years) obesity (Families Improving health Together [FIT]) could promote lower patient attrition (primary goal) and foster productive research in pediatric obesity (secondary goal). RESULTS: Data support the hypotheses. Over 15 months, FIT reported a >90% participant retention (p < 0.001 vs. expected rate based on other studies of similar programs). Though 90% of children had at least one adiposity-related comorbidity and 70% had at least two, there was no need for additional subspecialist visits with cardiologists, endocrinologists, gastroenterologists, or molecular geneticists. Three abstracts were presented at national meetings, and two manuscripts were published all with junior faculty as primary authors. CONCLUSION: This pilot study suggests that an integrated multispecialty/interdisciplinary approach to children with obesity improves patient retention and can be integrated successfully with research.

Exercise Capacity and Predictors of Performance After Fontan: Results from the Pediatric Heart Network Fontan 3 Study.

Impaired exercise following Fontan is a surrogate of morbidity. Single-center longitudinal data exist, but there is a lack of contemporary multi-center data. Ramp cycle ergometry was re-performed in consented participants who had originally participated in the Pediatric Heart Network's Fontan cross-sectional study. Annualized change was evaluated at maximal and submaximal exercise. Associations between these outcomes and patient characteristics were analyzed. There were 336 participants in Fontan 3, mean age 23.2 years. Paired measurements of peak oxygen consumption (peak VO2) were available for 95; peak exercise data at Fontan 3 were available for 275. Percent-predicted peak VO2 declined by 0.8 ± 1.7% per year (p < 0.001). At Fontan 3, the lowest performing peak VO2 tertile had the highest rate of overweight and obesity (p < 0.001). Female gender was more prevalent in the highest performing tertile (p = 0.004). Paired data at the ventilatory anaerobic threshold (VO2 at VAT) were available for 196; VAT data at Fontan 3 were available for 311. Percent-predicted VO2 at VAT decreased by 0.8 ± 2.6% per year (p < 0.001). At Fontan 3, VO2 at VAT was better preserved than peak VO2 across all tertiles, with higher rates of overweight and obesity in the lower performing group (p = 0.001). Female gender (p < 0.001) and left ventricular morphology (p = 0.03) were associated with better performance. Submaximal exercise is better preserved than maximal in the Fontan population, but declined at the same rate over the study period. The overall longitudinal rate of decline in exercise performance is slower than what has been described previously.

Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.

BACKGROUND: Approximately 25% of all patients with non-small-cell lung cancer present with resectable stage IB-IIIA disease, and although perioperative chemotherapy is the standard of care, this treatment strategy provides only modest survival benefits. On the basis of the activity of immune checkpoint inhibitors in metastatic non-small-cell lung cancer, we designed a trial to test the activity of the PD-L1 inhibitor, atezolizumab, with carboplatin and nab-paclitaxel given as neoadjuvant treatment before surgical resection. METHODS: This open-label, multicentre, single-arm, phase 2 trial was done at three hospitals in the USA. Eligible patients were aged 18 years or older and had resectable American Joint Committee on Cancer-defined stage IB-IIIA non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1, and a history of smoking exposure. Patients received neoadjuvant treatment with intravenous atezolizumab (1200 mg) on day 1, nab-paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL per min) on day 1, of each 21-day cycle. Patients without disease progression after two cycles proceeded to receive two further cycles, which were then followed by surgical resection. The primary endpoint was major pathological response, defined as the presence of 10% or less residual viable tumour at the time of surgery. All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT02716038, and is ongoing but no longer recruiting participants. FINDINGS: Between May 26, 2016, and March 1, 2019, we assessed 39 patients for eligibility, of whom 30 patients were enrolled. 23 (77%) of these patients had stage IIIA disease. 29 (97%) patients were taken into the operating theatre, and 26 (87%) underwent successful R0 resection. At the data cutoff (Aug 7, 2019), the median follow-up period was 12·9 months (IQR 6·2-22·9). 17 (57%; 95% CI 37-75) of 30 patients had a major pathological response. The most common treatment-related grade 3-4 adverse events were neutropenia (15 [50%] of 30 patients), increased alanine aminotransferase concentrations (two [7%] patients), increased aspartate aminotransferase concentration (two [7%] patients), and thrombocytopenia (two [7%] patients). Serious treatment-related adverse events included one (3%) patient with grade 3 febrile neutropenia, one (3%) patient with grade 4 hyperglycaemia, and one (3%) patient with grade 2 bronchopulmonary haemorrhage. There were no treatment-related deaths. INTERPRETATION: Atezolizumab plus carboplatin and nab-paclitaxel could be a potential neoadjuvant regimen for resectable non-small-cell lung cancer, with a high proportion of patients achieving a major pathological response, and manageable treatment-related toxic effects, which did not compromise surgical resection. FUNDING: Genentech and Celgene.

Predicting Peak Oxygen Uptake From the 6-Minute Walk Test in Patients With Pulmonary Hypertension.

PURPOSE: To determine whether the 6-minute walk test (6MWT) is a predictor of peak oxygen uptake ((Equation is included in full-text article.)O2) in patients with idiopathic pulmonary arterial hypertension (IPAH). METHODS: A total of 157 patients treated for IPAH completed a 6MWT in accordance with American Thoracic Society standards. Heart rate, pulse oximetry, and Borg rating of perceived exertion were determined at baseline and posttest. A cardiopulmonary exercise test (CPET) was performed on a cycle ergometer using a ramp protocol. Participants were stratified post hoc by age into 3 groups: children (n = 26), adolescents (n = 49), and adults (n = 82). Multiple linear regression analysis was performed to predict peak (Equation is included in full-text article.)O2 from the 6MWT. RESULTS: The regression equation generated for the children was the only model to strongly predict peak (Equation is included in full-text article.)O2 (r = 0.87; P < .001). Similar models for adolescent (r = 0.59; P < .001) and adult groups (r = 0.68; P < .001) did not achieve the same level of correlation. CONCLUSION: Six-Minute Walk Test was able to accurately predict peak (Equation is included in full-text article.)O2 in children (6-12 years) with IPAH; however, the model was weaker for predicting peak (Equation is included in full-text article.)O2 in older populations. These findings suggest that 6MWT may be as valid a test for predicting peak (Equation is included in full-text article.)O2 in children with IPAH as CPET measured peak (Equation is included in full-text article.)O2. In older IPAH populations, CPET is the only reliable method for the evaluation of peak (Equation is included in full-text article.)O2.

Cardiopulmonary exercise function among patients undergoing transcatheter pulmonary valve implantation in the US Melody valve investigational trial.

OBJECTIVES: We assessed the hypothesis that there is an improvement in clinical and physiologic parameters of cardiopulmonary exercise testing (CPET) after implantation of a transcatheter pulmonary valve (TPV). BACKGROUND: Transcatheter pulmonary valve provides a new tool for treating conduit stenosis and regurgitation in patients with right ventricle (RV) to pulmonary artery conduit dysfunction. METHODS: Patients who underwent a TPV placement between January 2007 and January 2010 (N = 150) were investigated with a standardized CPET protocol before and at 6 months after TPV placement. Cardiopulmonary exercise testing was performed on a mechanically braked cycle ergometer with respiratory gas exchange analysis. RESULTS: Six months post TPV, small but statistically significant improvements were observed in the maximum workload (65.0% ± 18.8% to 68.3% ± 20.3% predicted, P < .001) and the ratio of minute ventilation to CO(2) production at the anaerobic threshold (30.8 ± 4.7 to 29.1 ± 4.1, P < .001). There was no significant change in peak oxygen consumption (VO(2)). Patients with pre-TPV hemodynamics consistent with RV dysfunction and patients with a lower pre-TPV peak VO(2) tended to have the greatest improvement in peak VO(2). The correlation between TPV-related improvements in peak VO(2) and baseline clinical variables were weak, however, and these variables could not be used to reliably identify patients likely to have improved peak VO(2) after TPV. CONCLUSION: In patients with RV to pulmonary artery conduit dysfunction, TPV is associated with modest improvement in exercise capacity and gas exchange efficiency during exercise.

Cardiopulmonary exercise testing and six-minute walk correlations in pulmonary arterial hypertension.

In a clinical trial of 178 patients with pulmonary arterial hypertension, treatment improved the 6-minute walk (6MW) distance but not the peak VO2. To clarify this discrepancy, we examined the exercise data from all study sites. Patients received either the endothelin receptor antagonist sitaxsentan or placebo and underwent serial 6MW and cardiopulmonary exercise testing (CPET). In 518 pairs of body weight-adjusted and unadjusted 6MW and CPET data, the correlation between 6MW and peak VO2 was 0.48. In the 4 sites with the highest overall correlation at baseline (r = 0.62 compared with 0.46 for the other 19 sites, p = 0.04), the correlations at baseline (0.66) and at week 12 (0.65) were similar (p = 0.90). However, the correlation increased significantly from baseline (0.34) to week 12 (0.54, p = 0.0005) for the other 19 sites. The correlations between weight-adjusted 6MW distance and peak VO2 for all centers (0.76) were significantly higher than the unadjusted correlations (0.48, p < 0.0001). Improvement in the correlations over time between the 6MW and CPET data at less-experienced sites was most consistent with improved technical skill with increasing experience. Weight adjustment of the 6MW improved its correlation with peak VO2. In conclusion, in future multicenter trials, CPET expertise should be validated at all sites before subject enrollment.

New predictors of outcome in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (PAH) is a rare disease with a poor prognosis. New therapies have improved the outcome of this condition; accordingly, the factors that determine outcome may have changed. We aimed to identify determinants of survival in a cohort of consecutive patients with PAH: which was idiopathic, familial, or associated with anorexigen use. We performed a retrospective cohort study of 84 consecutive patients with PAH who underwent initial evaluation at our center from January 1994 to June 2002. The primary outcome was death or lung transplantation. Survival at 1, 3, and 5 [corrected] years was 87%, 75%, and 61%, respectively. Multivariate analysis showed that being of African-American or Asian descent was associated with an increased risk of death. Warfarin use was associated with a reduced risk of death. Higher serum albumin and cardiac index and acute vasoreactivity were independently associated with improved survival. These data suggest that the determinants of outcome have changed. Race is identified as a new risk factor, which may be attributable to biologic or socioeconomic differences. Cardiac function and acute reactivity of the pulmonary vascular bed remain strong independent predictors of outcome.

Identical twins with primary pulmonary hypertension: beraprost vs epoprostenol.

BACKGROUND: The course of 12-year-old, homozygotic twins with primary pulmonary hypertension (PPH) treated with different vasoactive agents, beraprost vs epoprostenol, is described. METHODS: Clinical, exercise, and hemodynamic assessments were made at baseline, and at 9 months and 24 months of treatment. FINDINGS: Twin A had a rapid improvement with epoprostenol. In contrast, twin B, initially treated with beraprost, had progressive worsening with subsequent improvement on epoprostenol. INTERPRETATION: Epoprostenol was efficacious for identical twins with PPH. A 9-month delay in initiating epoprostenol for twin B did not appear to have irreversible short-term detrimental effects.