Allison, Thomas G.

Background: COVID-19 reveals new manifestations not only in the acute phase but also in the long term. The latter is what has been termed as ‘post acute sequelae of SARS-CoV-2 infection’ (PASC) — or “long COVID”— with dyspnea as one of its hallmarks. Cardiopulmonary stress testing (CPET) is increasingly being used to better evaluate such patients. Objective: To compare CPET findings of long COVID patients versus non-COVID patients with undifferentiated dyspnea on exertion seen at Mayo Clinic. Methods: A cohort study was carried out using Mayo Clinic’s exercise testing database. The study group included 77 PASC patients confirmed by a positive antigen or PCR test with no prior history of heart or lung disease. PASC patients were compared to 766 non-COVID patients with unspecified dyspnea without known diagnosis of cardiac or pulmonary disease. ANOVA according to the general linear model and Pearson’s Chi square were used for the bivariate analysis of the quantitative and categorical variables, respectively. Analyses were controlled for age, sex, and beta blocker use as appropriate. Both HR and SBP at rest and peak exercise were significantly different between groups, although the absolute differences were small. Results: Compared with the control group, the post-COVID patients were younger (mean age 47 SD ±14.9 years versus 50.5 SD ±10.1 years) and more likely to be female (70.1% (54 of 77) vs 57.6% (441 of 766)). Although there were many significant differences in the CPET results, the most outstanding were a lower FAC (73 SD ±19.4% vs 85.2 SD ±20.8%) and peak VO2 (22 SD ±6.4 ml/kg/min vs 25.8 SD ±7.37 ml/kg/min) in the study group (p<.0001). Also, CNS changes during CPET were reported at higher rates (19.5% (15 of 77) vs 11.4% (87 of 766)) while dyspnea at lower rates (55.8% (43 of 77) vs 65.7% (503 of 766)) in post-COVID patients (p=0.02). When adjusting for age and sex, weight was significantly higher in the study group (p=0.03) although the absolute difference was modest and BMI remained not significant. PFTs did not suggest any pulmonary abnormalities. Conclusions: We identified a high rate of severe exercise limitation among long COVID patients. Young women may be at higher risk for these complications. Pre-exercise PFTs and absence of objective respiratory limitation during CPET argue against a primary pulmonary cause of the observed limitations, though evaluation of cardiac, autonomic, and muscular impairment is pending. Further studies are warranted to untangle the physiologic abnormalities responsible for these observations.

Background: CHA2DS2-VASc score has been shown to predict occurrences of incident stroke in patients with history of atrial fibrillation (A-Fib)/ Flutter. However, data on whether if CHA2DS2-VASc score would predict incidence of stroke in patients without A-Fib/ Flutter is less clear. Methods: From 1993 through 2010, all patients undergoing a clinically indicated treadmill exercise test (TMET) at the Mayo Clinic, Rochester, MN were identified (N= 76,857). From this, Olmsted and neighboring counties residents were selected (N=14,095). From this, patients with age <18 years; prior history of valvular heart disease or A-Fib/ Flutter were excluded. Patient undergoing only Bruce or accelerated Naughton protocols on TMET were considered. Patients were stratified into 4 groups at baseline based on CHA2DS2-VASc score as determined at the time of TMET; group-0 score=0; group-I=1; group-2=2; group-3≥3. Patients were prospectively followed from the date of TMET until end of January 2016 for occurrence of incident stroke (ischemic and hemorrhagic). Stroke diagnosis was ascertained through retrospective chart review. Traumatic intracranial bleed was not considered. Proportional hazard regression modeling was done to assess relationship of CHA2DS2-VASc score with the stroke outcome while adjusting for METs achieved, sex, obesity, smoking status, and other relevant risk factors. Results: Final study population comprised of 12,624 patients with female comprising 37% of the cohort. Mean age in our study group was 52.2 ± 12.8 years. During an overall median follow-up of 14 (8 to 17) years, 1,255 (9.9%) patients developed incident stroke. While using CHA2DS2-VASc group-3 as referent, patients in CHA2DS2-VASc group-0 [0.18(0.14-0.23, p<.001)], group-1[0.33 (0.28-0.39, p<.001)], and group-2 [0.50 (0.43-0.58, p<.001)] were at significantly lower risk of developing stroke. Each increase of one point on the CHA2DS2-VASc scale was associated with a 51% [1.51(1.45-1.58, p<.001)] increase in incidence of stroke. Conclusion: CHA2DS2-VASc score predicts incidence of stroke in patients without history of A-Fib/ Flutter.

Background: We conducted this study to assess the safety of symptom-limited cardiopulmonary exercise testing (CPX) in patients with varying severity of aortic stenosis (AS). We hypothesized that exercise testing would be safe, as defined by a rates for all-cause death of <0.01% and rate of nonfatal major cardiovascular (CV) events <0.1% within 24 hours of CPX. Secondary purpose of this study was to determine the frequency of complications during CPX. Methods: This cohort study was carried out with 308 consecutive patients with varying degree of AS (as determined by standard echocardiographic criteria) with no or equivocal symptoms who were referred for clinically indicated cardiopulmonary testing between 1994 and 2009. We did not include patients with pending or completed heart transplant, or ventricular assist device implantation. These patients underwent standard symptom limited CPX, and continuous monitoring of heart rate, blood pressure, and electrocardiogram was performed. Complications recorded included death, non-fatal major CV events (cardiac arrest, symptomatic and sustained ventricular or atrial tachycardia, and syncope), and minor events such as hypotension, non-sustained atrial and ventricular arrhythmias, positive exercise ECG and anginal pain. Results: The mean age of patients was 66 ± 14 years, and 252 (82%) were males. The number of patients with mild, moderate and severe AS were 44 (14%), 138 (49%), and 126 (41%) respectively. No death or major CV event occurred during or within 24 hours of CPX. Eleven patients developed supraventricular arrhythmias without compromising hemodynamic status, and one had asymptomatic non-sustained ventricular tachycardia. Detailed description of complications is presented in the Table 1 . Conclusion: Our results show that symptom-limited CPX is safe among AS patients with no or equivocal symptoms based on no deaths or major CV events in our cohort. Minor complications occurred in 110 patients (36%). Table 1 Mild AS (n=44) Moderate AS (n=138) Severe AS (n=126) Age 61.7 ± 15.3 66.5 ± 13.86 67.89 ± 12.74 Males 36 (81%) 128 (83%) 96 (85%) Test protocol O2 protocol 39 (86%) 123 (89%) 104 (82%) Other 5 15 22 Reason for termination Symptom-limited 41 (93%) 114 (82%) 96 (76%) Other 3 24 30 Chest pain None 41 (93%) 122 (88%) 117 (93%) Non-cardiac 0 2 0 Non-anginal 0 2 0 Anginal 2 14 9 Treadmill ECG interpretation Negative 27 (61%) 67 (49%) 45 (37%) Non-diagnostic 14 48 58 Positive 3 23 23 Ventricular arrhythmia None 42 (95%) 134 (97%) 122 (97%) 3-5 beats VT 2 3 4 NSVT 0 1 0 Supraventricular arrhythmia None 42 (95%) 135 (97%) 120 (95%) SVT ≤ 30 sec 2 3 4 SVT > 30 sec 0 0 1 Afib 0 0 1 BP response Normal 41 (93%) 117 (85%) 93 (74%) Hypotensive 3 21 33 AS = Aortic Stenosis, ECG = Electrocardiogram, VT = Ventricular tachycardia, NSVT = Non-sustained ventricular tachycardia, SVT = Supraventricular tachycardia, Afib = Atrial fibrillation, BP = Blood pressure

Introduction: Patients with hypertrophic cardiomyopathy (HCM) have lower peak oxygen uptake (VO2) than healthy peers. The mechanism of peak VO2 limitation in HCM has not been fully elucidated. Hypothesis: We assessed the hypothesis that resting echocardiographic parameters are predictive of peak VO2 in HCM. Methods: A retrospective review of adult HCM patients seen at a tertiary referral center from 2006-2012 was performed. Patients who underwent a comprehensive echocardiogram and cardiopulmonary treadmill exercise test within 1 week were included. Multivariate modeling was used to identify predictors of peak VO2 adjusting for age, sex, body mass index, beta blocker use, diabetes, smoking, systolic blood pressure, and obstructive HCM. Results: Five hundred and forty one patients met the inclusion criteria. The average age was 52 +/- 0.65 years, 62% were male, 78% had obstructive HCM, and 42% were NYHA class III or IV. Independent predictors of peak VO2 included averaged left ventricular (LV) longitudinal peak systolic strain (p<0.01) and right ventricular systolic pressure (RVSP) (p<0.01) (Figure 1). Obstructive versus non-obstructive HCM, grade of diastolic dysfunction, LV mass and wall thickness, left atrial volume index, right ventricular dysfunction and moderate or greater mitral or tricuspid regurgitation were not independent predictors of peak VO2. Conclusions: In conclusion, higher RVSP and less negative LV longitudinal peak systolic strain were moderate independent predictors of lower peak VO2. These findings confirm the hypothesis that resting echocardiographic parameters are predictive of peak VO2 in HCM. Further study of the relationship between echocardiographic findings and outcomes on cardiopulmonary exercise testing may help elucidate the mechanisms of exercise limitation in HCM.

Introduction: Impaired peak VO2 and obesity are known predictors of morbidity and mortality in Hypertrophic Cardiomyopathy (HCM). The purpose of this study is to determine the degree of exercise impairment due to excess weight in patients with HCM. Methods: Adult HCM patients who underwent cardiopulmonary treadmill testing at our tertiary referral center from 2006 - 2012 and had consented to research participation were identified retrospectively. Percent predicted peak VO2 was calculated by the Astrand formula for men and the Jones formula for women which adjust for age and gender. Baseline echocardiographic features obtained within 1 week of exercise testing and % predicted peak VO2 were compared among four groups of patients stratified by body mass index (BMI). Results: 510 patients were identified, with a mean age at diagnosis of 44.3 ± 16.1 years, 186 (36.5%) female. Mean BMI at the time of cardiopulmonary exercise testing was 29.7 ± 5.3 and 227 (44.6%) patients had a BMI ≥ 30. Overweight and obese patients were older and were more likely to be male than their normal weight peers. However, there was no significant difference in ejection fraction (EF), resting left ventricular outflow tract gradient, right ventricular systolic pressure (RVSP), or septal thickness among the groups. HCM patients show impaired peak VO2 across all BMI groups. While peak VO2 increased progressively across BMI groups consistent with greater O2 demand generated by higher body weight, the adjusted peak VO2 in mL/kg/min fell progressively, indicating progressively greater performance impairment with increasing BMI despite similar degrees of cardiac impairment (p <0.0001) (Table 1). Conclusion: Increased BMI is associated with reduced exercise performance in a graded manner in HCM patients independent of cardiac impairment identified on echocardiography.

Introduction: Cardiovascular disease (CVD) is the leading cause of morbidity/mortality in the US. Despite being a class 1A evidence-based recommendation, secondary prevention efforts in the period following cardiac rehabilitation (CR) lack a proven and successful intervention. A previously validated digital health intervention (DHI) delivered Mayo Clinic’s CR, including educational material, tracking CVD indices, and diet/exercise adherence, for 3 months after usual CR. Hypothesis: We hypothesized DHI use would improve CVD risk factors and rehospitalizations/ emergency department (ED) visits. Methods: Patients undergoing usual Mayo Clinic CR were recruited to use the application following usual CR (n=17) and compared to a similar cohort undergoing standard post-CR care, but not assigned to the application (n=11). DHI patients performed daily informational tasks, entered their own risk factor information (weight, blood pressure (BP), glucose, lipids, physical activity, and diet) at baseline and for three months post-CR. Changes in risk factors, re-hospitalizations/ED visits were assessed after three months. Results: There were no differences in baseline demographics between the two groups. There was no difference in weight change between the two groups during the three months of usual CR, yet in the three months following usual CR the DHI group had significant reductions in weight (-2.5±3.8 kg, p=0.04) and systolic BP (-12.6±12.4 mmHg, p=0.001) compared to the control group. The DHI group also showed significantly lower rate of rehospitalizations/ED visits (-28%, p=0.04, Figure). Conclusions: A DHI post-CR program can enhance secondary prevention strategies compared to standard post-CR care by augmenting weight and BP reduction and reducing the healthcare burden of repeat CVD events. This study thus supports development and implementation of DHI programs.

BACKGROUND: Peak flow testing is a common procedure performed in ambulatory care. There are currently no data regarding aerosol generation during this procedure. Given the ongoing debate regarding the potential for aerosol transmission of SARS-CoV-2, we aimed to quantify and characterize aerosol generation during peak flow testing. METHODS: Five healthy volunteers performed peak flow maneuvers in a particle-free laboratory space. Two devices continuously sampled the ambient air during the procedure. One device can detect ultrafine particles 0.02–1 μ m in diameter, while the second device can detect particles 0.3, 0.5, 1.0, 2.0, 5.0, and 10 μ m in diameter. Five different peak flow meters were compared to ambient baseline during masked and unmasked tidal breathing. RESULTS: Ultrafine particles (0.02–1 μ m) were generated during peak flow measurement. There was no significant difference in ultrafine particle mean concentration between peak flow meters ( P = .23): Respironics (1.25 ± 0.47 particles/mL), Philips (3.06 ± 1.22), Clement Clarke (3.55 ± 1.22 particles/mL), Respironics Low Range (3.50 ± 1.52 particles/mL), and Monaghan (3.78 ± 1.31 particles/mL). Ultrafine particle mean concentration with peak flow testing was significantly higher than masked (0.22 ± 0.29 particles/mL) and unmasked tidal breathing (0.15 ± 0.18 particles/mL, P = .01), but the ultrafine particle concentrations were small compared to ambient particle concentrations in a pulmonary function testing room (89.9 ± 8.95 particles/mL). CONCLUSIONS: In this study, aerosol generation was present during peak flow testing, but concentrations were small compared to the background particle concentration in the ambient clinical environment. Surgical masks and eye protection are likely sufficient infection control measures during peak expiratory flow testing in asymptomatic patients with well controlled respiratory symptoms, but COVID-19 testing remains prudent in patients with acute respiratory symptoms prior to evaluation and peak expiratory flow assessment while the community prevalence of SARS-CoV-2 cases remains high.

We sought to update norms for peak systolic blood pressure (SBP) on the graded exercise test and examine its prognostic value in patients without baseline cardiovascular disease. Mayo graded exercise test data (1993–2010) were reviewed for nonimaging tests using Bruce protocol, selecting Minnesota residents 30 to 79 years without baseline cardiovascular disease. We formed a pure cohort of patients without factors significantly affecting peak SBP to determine peak SBP percentile norms by age and sex. Then we divided the full cohort of patients into 5 groups based on peak SBP percentiles: low (<10th), borderline low (10th–25th), referent (25th–75th), borderline high (75th–90th), and high (>90th). The relationship between peak SBP and mortality was tested using Cox regression adjusting for age, sex, and comorbidities affecting peak SBP or mortality. We identified 20 760 eligible patients with 7313 females (35%) and mean age 51.5±10.7 years. Our pure cohort included 7810 patients. Over 12.5±5.0 years follow-up, there were 1582 deaths, including 541 cardiovascular deaths. In the fully adjusted model, low-peak SBP was associated with increased total mortality (heart rate, 1.41 [1.19–1.66], P <0.0001) and cardiovascular mortality (heart rate, 1.54 [1.16–2.03], P =0.001), while borderline low-peak SBP was associated with increased cardiovascular mortality only (heart rate, 1.36 [1.02–1.81], P =0.027). High peak SBP was associated with increased total mortality only in the age-sex adjusted model (heart rate, 1.18 [1.02–1.36], P =0.026), not after full adjustment. We conclude that low exercise peak SBP is an independent predictor of higher total and cardiovascular mortality.

Abstract Background Dyspnea on exertion (DOE) is defined as a subjective experience of breathing discomfort that consists of qualitatively distinct sensations (Effort/work of breathing, Chest tightness, Air hunger) that vary in intensity elicited by physical activity. Although DOE is a common presenting symptom in patients pertaining to cardiovascular and respiratory disorders, its prognostic importance in patients with no prior cardiovascular (CV) or respiratory disorders is unclear. Purpose The purpose of this study is to determine the prognostic significance of dyspnea on exertion (DOE) in patients with no prior diagnosis of CV or respiratory disorders. Methods We reviewed the Mayo Integrated Stress Center database for the period September 1993 through November 2010. Residents of Minnesota with no known heart disorders and no known history of COPD or other respiratory disorders were included in the study. Patients with abnormal ECG findings were excluded to rule out possible undiagnosed CV disorders. Limiting symptoms of DOE with reduced exercise capacity (FAC&lt;90%). Our primary outcome was mortality which was adjusted for age, sex, smoking history, diabetes, hypertension, obesity, negative chronotropic medications. Statistical analysis was performed to evaluate hazard ratio using Cox regression models in SAS Studio. Results A total of 101,455 exercise tests were reviewed to identify 18960 patients (female = 6755, 35.6%) who met the study criteria. Mean age at the time of referral was 51.2±10 years (mean ± SD) and mean follow-up was 12±10 years (mean ± SD). There were 1331 (7%) deaths from all causes, out of which 368 (27.6%) deaths are from DOE patients, and there were 428 (2.2%) deaths from cardiac causes, out of which 141 (32.9%) deaths are from DOE patients. We found that DOE was an independent predictor of mortality from all causes with hazard ratio [95% CI] = 1.690 [1.488–1.918], p≤0.0001, and from cardiac causes with hazard ratio [95% CI] = 1.997 [1.613–2.473], p≤0.0001. Product-limit survival estimates of patients with and without DOE are shown in Figure 1. Conclusion Based on our study findings, we conclude that dyspnea on exertion is an independent predictor of mortality in patients with no baseline CV or respiratory disorders. Patients presenting with dyspnea alone as a presenting compliant should be evaluated thoroughly and treated accordingly to reduce the associated mortality outcomes. Figure 1. Kaplan-Meier Plot Funding Acknowledgement Type of funding source: None

Background Right bundle‐branch block (RBBB) occurs in 0.2% to 1.3% of people and is considered a benign finding. However, some studies have suggested increased risk of cardiovascular morbidity and mortality. We sought to evaluate risk attributable to incidental RBBB in patients without prior diagnosis of cardiovascular disease (CVD). Methods and Results We reviewed the Mayo Clinic Integrated Stress Center database for exercise stress tests performed from 1993 to 2010. Patients with no known CVD—defined as absence of coronary disease, structural heart disease, heart failure, or cerebrovascular disease—were selected. Only Minnesota residents were included, all of whom had full mortality and outcomes data. There were 22 806 patients without CVD identified; 220 of whom (0.96%) had RBBB, followed for 6 to 23 years (mean 12.4±5.1). There were 8256 women (36.2%), mean age was 52±11 years; and 1837 deaths (8.05%), including 645 cardiovascular‐related deaths (2.83%), occurred over follow‐up. RBBB was predictive of all‐cause (hazard ratio [HR], 1.5; 95% CI, 1.1–2.0; P =0.0058) and cardiovascular‐related mortality (HR,1.7; 95% CI, 1.1–2.8; P =0.0178) after adjusting for age, sex, diabetes mellitus, hypertension, obesity, current and past history of smoking, and use of a heart rate‐lowering drug. Patients with RBBB exhibited more hypertension (34.1% versus 23.7%, P <0.0003), decreased functional aerobic capacity (82±25% versus 90±24%; P <0.0001), slower heart rate recovery (13.5±11.5 versus 17.1±9.4 bpm; P <0.0001), and more dyspnea (28.2% versus 22.4%; P <0.0399) on exercise testing. Conclusions Patients with RBBB without CVD have increased risk of all‐cause mortality, cardiovascular‐related mortality, and lower exercise tolerance. These data suggest RBBB may be a marker of early CVD and merit further prospective evaluation.