Paul Chase

Development of a Ventilatory Classification System in Patients With Heart Failure

Background— Ventilatory efficiency, commonly assessed by the minute ventilation (&OV0312;e)–carbon dioxide production (&OV0312;co2) slope, is a powerful prognostic marker in the heart failure population. The purpose of the present study is to refine the prognostic power of the &OV0312;e/&OV0312;co2 slope by developing a ventilatory class system that correlates &OV0312;e/&OV0312;co2 cut points to cardiac-related events. Methods and Results— Four hundred forty-eight subjects diagnosed with heart failure were included in this analysis. The &OV0312;e/&OV0312;co2 slope was determined via cardiopulmonary exercise testing. Subjects were tracked for major cardiac events (mortality, transplantation, or left ventricular assist device implantation) for 2 years after cardiopulmonary exercise testing. There were 81 cardiac-related events (64 deaths, 10 heart transplants, and 7 left ventricular assist device implantations) during the 2-year tracking period. Receiver operating characteristic curve analysis revealed the overall &OV0312;e/&OV0312;co2 slope classification scheme was significant (area under the curve: 0.78 [95% CI, 0.73 to 0.83], P<0.001). On the basis of test sensitivity and specificity, the following ventilatory class system was developed: (1) ventilatory class (VC) I: ≤29; (2) VC II: 30.0 to 35.9; (3) VC III: 36.0 to 44.9; and (4) VC IV: ≥45.0. The numbers of subjects in VCs I through IV were 144, 149, 112, and 43, respectively. Kaplan-Meier analysis revealed event-free survival for subjects in VC I, II, III, and IV was 97.2%, 85.2%, 72.3%, and 44.2%, respectively (log-rank 86.8; P<0.001). Conclusions— A multiple-level classificatory system based on exercise &OV0312;e/&OV0312;co2 slope stratifies the burden of risk for the entire spectrum of heart failure severity. Application of this classification is therefore proposed to improve clinical decision making in heart failure.

Impact of Cardiorespiratory Fitness on the Obesity Paradox in Patients With Heart Failure

OBJECTIVE To determine the impact of cardiorespiratory fitness (FIT) on survival in relation to the obesity paradox in patients with systolic heart failure (HF). PATIENTS AND METHODS We studied 2066 patients with systolic HF (body mass index [BMI] ≥18.5 kg/m(2)) between April 1, 1993 and May 11, 2011 (with 1784 [86%] tested after January 31, 2000) from a multicenter cardiopulmonary exercise testing database who were followed for up to 5 years (mean ± SD, 25.0±17.5 months) to determine the impact of FIT (peak oxygen consumption <14 vs ≥14 mL O2 ∙ kg(-1) ∙ min(-1)) on the obesity paradox. RESULTS There were 212 deaths during follow-up (annual mortality, 4.5%). In patients with low FIT, annual mortality was 8.2% compared with 2.8% in those with high FIT (P<.001). After adjusting for age and sex, BMI was a significant predictor of survival in the low FIT subgroup when expressed as a continuous (P=.03) and dichotomous (<25.0 vs ≥25.0 kg/m(2)) (P=.01) variable. Continuous and dichotomous BMI expressions were not significant predictors of survival in the overall and high FIT groups after adjusting for age and sex. In patients with low FIT, progressively worse survival was noted with BMI of 30.0 or greater, 25.0 to 29.9, and 18.5 to 24.9 (log-rank, 11.7; P=.003), whereas there was no obesity paradox noted in those with high FIT (log-rank, 1.72; P=.42). CONCLUSION These results indicate that FIT modifies the relationship between BMI and survival. Thus, assessing the obesity paradox in systolic HF may be misleading unless FIT is considered.

A cardiopulmonary exercise testing score for predicting outcomes in patients with heart failure

OBJECTIVE The aim of this study is to evaluate the predictive accuracy of a cardiopulmonary exercise test (CPX) score. BACKGROUND Cardiopulmonary exercise test responses, including peak VO(2), markers of ventilatory inefficiency (eg, the VE/VCO(2) slope and oxygen uptake efficiency slope [OUES]), and hemodynamic responses, such as heart rate recovery (HRR) and chronotropic incompetence (CRI) are strong predictors of outcomes in patients with heart failure (HF). However, there is a need for simplified approaches that integrate the additive prognostic information from CPX. METHODS At 4 institutions, 710 patients with HF (568 male/142 female, mean age 56 +/- 13 years, resting left ventricular ejection fraction 33 +/- 14%) underwent CPX and were followed for cardiac-related mortality and separately for major cardiac events (death, hospitalization for HF, transplantation, left ventricular assist device implantation) for a mean of 29 +/- 25 months. The age-adjusted prognostic power of peak VO(2), VE/VCO(2) slope, OUES (VO(2) = a log(10)VE + b), resting end-tidal carbon dioxide pressure (PetCO(2)), HRR, and CRI were determined using Cox proportional hazards analysis, optimal cutpoints were determined, the variables were weighted, and a multivariate score was derived. RESULTS There were 175 composite outcomes. The VE/VCO(2) slope (> or =34) was the strongest predictor of risk and was attributed a relative weight of 7, with weighted scores for abnormal HRR (< or =6 beats at 1 minute), OUES (>1.4), PetCO(2) (<33 mm Hg), and peak VO(2) (< or =14 mL kg(-1) min(-1)) having scores of 5, 3, 3, and 2, respectively. Chronotropic incompetence was not a significant predictor and was excluded from the score. A summed score >15 was associated with an annual mortality rate of 27% and a relative risk of 7.6, whereas a score <5 was associated with a mortality rate of 0.4%. The composite score was the most accurate predictor of cardiovascular events among all CPX responses considered (concordance indexes 0.77 for mortality and 0.75 for composite outcome composed of mortality, transplantation, left ventricular assist device implantation, and HF-related hospitalization). The summed score remained significantly associated with increased risk after adjusting for age, gender, body mass index, ejection fraction, and cardiomyopathy type. CONCLUSION A multivariable score based on readily available CPX responses provides a simple and integrated method that powerfully predicts outcomes in patients with HF.

Fat Distribution and End-Expiratory Lung Volume in Lean and Obese Men and Women

BACKGROUND Although obesity significantly reduces end-expiratory lung volume (EELV), the relationship between EELV and detailed measures of fat distribution has not been studied in obese men and women. To investigate, EELV and chest wall fat distribution (ie, rib cage, anterior subcutaneous abdominal fat, posterior subcutaneous fat, and visceral fat) were measured in lean men and women (ie, < 25% body fat) and obese men and women (ie, > 30% body fat). METHODS All subjects underwent pulmonary function testing, hydrostatic weighing, and MRI scans. Data were analyzed for the men and women separately by independent t test, and the relationships between variables were determined by regression analysis. RESULTS All body composition measurements were significantly different among the lean and obese men and women (p < 0.001). However, with only a few exceptions, fat distribution was similar among the lean and obese men and women (p > 0.05). The mean EELV was significantly lower in the obese men (39 +/- 6% vs 46 +/- 4% total lung capacity [TLC], respectively; p < 0.0005) and women (40 +/- 4% vs 53 +/- 4% TLC, respectively; p < 0.0001) compared with lean control subjects. Many estimates of body fat were significantly correlated with EELV for both men and women. CONCLUSIONS In both men and women, the decrease in EELV with obesity appears to be related to the cumulative effect of increased chest wall fat rather than to any specific regional chest wall fat distribution. Also, with only a few exceptions, relative fat distribution is markedly similar between lean and obese subjects.

Obesity: Associations with Acute Mountain Sickness

Context A few small retrospective studies show associations between obesity and acute mountain sickness. Contribution This 24-hour study involving 9 obese and 10 nonobese men was conducted in a decompression chamber that simulated a rapid ascent to an altitude of 3658 m (12 000 ft). Obese men more often developed symptoms of mountain sickness and had lower nocturnal oxygen saturation values than did nonobese men. Cautions Although this elegant, short experiment suggests that obese men were more susceptible to acute mountain sickness, the study involved few people, simulated a steady rate of ascent, and did not simulate physical activity with altitude exposure. The Editors Rapid ascent from low to high altitude (above 2500 m or 8200 ft) often causes acute mountain sickness (AMS), a syndrome characterized by headache and other systemic symptoms, such as nausea, lassitude, and difficulty sleeping. The prevalence and severity of AMS depend on the speed of ascent, the altitude attained, preacclimatization, age, sex, exertion levels while at altitude, and the ventilatory response to acute hypoxia (1, 2). Few retrospective field studies of high altitude have reported that obesity, as evidenced by body mass index (BMI), might be associated with the development of AMS (3-7). However, this association has not been studied prospectively under controlled conditions at reasonably accessible altitudes or in individuals with mild to moderate obesity. We sought to determine whether obese individuals are more likely to develop AMS than nonobese individuals during decompression to a simulated altitude of 3658 m. We hypothesized that obese individuals were more susceptible to develop AMS than nonobese individuals during exposure to high altitudeinduced hypobaric hypoxia. Methods Participants Volunteers were recruited through local advertisements and were selected for participation on the basis of percentage body fat. Nonobese was defined as percentage body fat less than 25%. Obese was defined as a BMI of 30 kg/m2 or greater and percentage body fat of 30% or greater. None of the participants had a history of cardiovascular or respiratory abnormalities. No participant was taking long-term medications. All participants were nonsmokers. Nine obese men (mean age [SD], 35 8 years) and 10 nonobese men (mean age [SD], 34 8 years) were studied. All participants resided at sea level (100 m) in Dallas, Texas. One obese and three nonobese participants previously had mild AMS. One obese participant was exposed to a 2500-m altitude 4 days before this study; no other participant was exposed to a 1500-m or higher altitude before participating in the study. Each participant received both written and verbal explanations of the experiment before giving written consent. The Institutional Review Board of the University of Texas Southwestern Medical Center and Presbyterian Hospital of Dallas approved this study. Study Protocol The study was conducted in a large (40 ft long by 9 ft diameter) multiplace (room for >1 person) decompression chamber at the Institute for Exercise and Environmental Medicine in Dallas. The barometric pressure was held at 483 mm Hg, which is equivalent to an altitude of 3658 m (12 000 ft). The temperature (25 0.5 C), humidity (28% 1%), and concentration of CO2 (0.07% 0.02%) in the chamber were monitored continuously by trained medical staff. Four participants at a time were studied in the chamber during the 24 hours of exposure (Figure 3). Assessment of AMS According to guidelines established by the Lake Louise AMS consensus report (8), each participant completed an AMS self-report questionnaire at sea level (before decompression) and during decompression to 483 mm Hg at 6 hours, 12 hours, and 24 hours. The questionnaire included items for symptoms of headache, gastrointestinal symptoms, fatigue or weakness, dizziness or lightheadedness, and difficulty sleeping. Each symptom was graded on a scale from 0 to 3, with 0 representing no symptoms; 1, mild symptoms; 2, moderate symptoms; and 3, severe symptoms. A score of 15 was the maximum score possible. A self-score of 4 or more was an indication of AMS (8). This scoring system has been validated against the U.S. Army Environmental Symptoms Questionnaire, demonstrating similar sensitivity and specificity (9). Measurements of Sao 2 Daytime Sao 2 was measured by pulse oximetry (Ohmeda 3700 Pulse Oximeter, Datex-Ohmeda, Boulder, Colorado) at sea level and at 6 hours and 24 hours of simulated altitude. Nocturnal Sao 2 in each participant was continuously recorded in the chamber from 10:30 p.m. to 6:30 a.m. The mean nocturnal Sao 2 was calculated from values obtained every 30 minutes. Heart rate was measured at sea level and at altitude during the daytime and during sleep. Other Measurements Body composition was determined by hydrostatic weighing, and percentage body fat, fat mass, and lean mass were calculated. At sea level, all participants underwent standard spirometry (measuring lung volumes, maximal flow-volume loop, and maximal voluntary ventilation) and diffusing capacity of the lung in a whole-body plethysmograph (Model 6200, SensorMedics, Yorba Linda, California). Pulmonary function testing was performed according to the guidelines of the American Thoracic Society. Statistical Analysis Data are expressed as means (SD). The parameters of AMS score and Sao 2 were analyzed by a two-way analysis of variance (ANOVA) using SAS software, release 8.02 (SAS Institute, Inc., Cary, North Carolina), with repeated measures on one factor (altitude-time) and between-participant comparisons for the other factor (group, nonobese and obese). Comparisons were considered significant when the P value was less than 0.05. Role of the Funding Sources The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Participants The Table shows general characteristics of the participants. One participant in the obese group was removed from the chamber after 10 hours because of severe headache, nausea, and dizziness (AMS score, 8). As a result, this participant was not included in further analyses. Table. General Characteristics and Pulmonary Function of Participants at Baseline AMS Scores There was a significant interaction between altitude-time and group (P < 0.001) as a result of the two-way ANOVA. This indicated that the increase in AMS scores with altitude exposure was more pronounced in the obese participants (Figure 1). Overall, after 24 hours in the chamber, seven obese participants and four nonobese participants had an AMS score of 4 or more. The frequency of AMS symptoms at 24 hours in 18 participants was as follows: headache, 89%; gastrointestinal upset, 36%; fatigue and weakness, 36%; dizziness, 15%; and difficulty sleeping, 75%. Figure 1. Comparison of the acute mountain sickness ( AMS ) score at sea level and at simulated altitude for 24 hours in nonobese ( n = 10) and obese ( n = 8) participants. P Sao 2 There was also a significant interaction between altitude-time and group (P < 0.001) for Sao 2 as a result of the two-way ANOVA (Figure 2). This indicated that the decrease in Sao 2 with altitude exposure differed between the two groups. Figure 2. Comparison of Sao at sea level, during the daytime, and during sleep at night in nonobese ( n = 10) and obese ( n = 8) participants. o P Figure 3. Participants during simulated altitude exposure in decompression chamber. Discussion Our principal finding was that obese participants have higher AMS scores than nonobese participants during a 24-hour exposure to simulated altitude of 3658 m. Thus, obesity seems to be associated with the development of AMS. Also, the response of Sao 2 with exposure differed between nonobese and obese men; obese men had lower values than nonobese men. These findings suggest that impaired breathing during sleep may be an important pathophysiologic mechanism for the increased levels of AMS in obese individuals. Limitations Although our results suggest that obese individuals may be more susceptible to AMS, these results must be interpreted with caution. Possible limitations to generalization include the small sample size, the selected nature of the study sample, the narrow spectrum of obese participants studied, the steady rate of ascent, the lack of physical activity during altitude exposure, and the simulated environment in which the participants were studied. Obesity and AMS Obesity is characterized by an abnormally large adipose tissue mass. In particular, excess weight leads to the development of various pathophysiologic disorders and, specifically, cardiovascular and respiratory abnormalities. Obesity-related respiratory function abnormalities, such as sleep-disordered breathing and nocturnal hypercapnia and hypoxia, place obese individuals at risk for illness at higher altitudes (10-13). In addition, the prevalence of obesity in western society, especially in the United States (where 22% of the population has a BMI > 30 kg/m2 and roughly 30% of the population is overweight [14, 15]), further increases the potential for altitude-related difficulties at easily accessible high altitudes during recreational activities. A review of the literature revealed no prospective data on the effect of obesity on high-altitude illness. In our study, AMS scores increased with time during altitude exposure in both nonobese and obese participants, which is consistent with previous data demonstrating that AMS symptoms are common after 24 hours of rapid ascent to high altitude (1, 2). The severity of symptoms, however, significantly differed between nonobese and obese men, suggesting that the occurrences of AMS at high altitude may be closely related to increased body weight. Acute mountain sickness frequently occurs in travelers who rapidly ascend to an altitude of 2500 m without acclimatizing; the incidence and severity depend on the speed of asce

Determining the Preferred Percent-Predicted Equation for Peak Oxygen Consumption in Patients With Heart Failure

Background—Peak oxygen consumption (Vo2) is routinely assessed in patients with heart failure undergoing cardiopulmonary exercise testing. The purpose of the present investigation was to determine the prognostic ability of several established peak Vo2 prediction equations in a large heart failure cohort. Methods and Results—One thousand one hundred sixty-five subjects (70% males; age, 57.0±13.8 years; ischemic etiology, 43%) diagnosed with heart failure underwent cardiopulmonary exercise testing. Percent-predicted peak Vo2 was calculated according to normative values proposed by Wasserman and Hansen (equation), Jones et al (equation), the Cooper Clinic (below low fitness threshold), a Veteran’s Administration male referral data set (4 equations), and the St James Take Heart Project for women (equation). The prognostic significance of percent-predicted Vo2 values derived from the 2 latter, sex-specific equations were assessed collectively. There were 179 major cardiac events (117 deaths, 44 heart transplantations, and 18 left ventricular assist device implantations) during the 2-year tracking period (annual event rate, 10%). Measured peak Vo2 and all percent-predicted peak Vo2 calculations were significant univariate predictors of adverse events (&khgr;2≥31.9, P<0.001) and added prognostic value to ventilatory efficiency (VE/Vco2 slope), the strongest cardiopulmonary exercise testing predictor of adverse events (&khgr;2=150.7, P<0.001), in a multivariate regression. The Wasserman/Hansen prediction equation provided optimal prognostic information. Conclusions—Actual peak Vo2 and the percent-predicted models included in this analysis all were significant predictors of adverse events. It seems that the percent-predicted peak Vo2 value derived from the Wasserman/Hansen equations may outperform other expressions of this cardiopulmonary exercise testing variable.

The prognostic value of the heart rate response during exercise and recovery in patients with heart failure: Influence of beta-blockade

BACKGROUND The heart rate increase during exercise (DeltaHR) and heart rate recovery (HRR) have demonstrated prognostic value in several investigations, but its application in the heart failure (HF) population is limited, particularly in a beta-blocked (BB) cohort. METHODS Five-hundred and twenty subjects with HF underwent cardiopulmonary exercise testing to determine peak oxygen consumption (VO(2)), the minute ventilation/carbon dioxide production (VE/VCO(2)) slope, DeltaHR and HRR at 1 min (HRR(1)). RESULTS There were 79 cardiac-related deaths during the tracking period. A HRR(1) threshold of or=16 beats/min was a significant prognostic marker in the overall group (hazard ratio: 4.6, 95% CI: 2.8-7.5, p<0.001) as well as no-BB (hazard ratio: 9.1, 95% CI: 4.1-20.2, p<0.001) and BB (hazard ratio: 2.9, 95% CI: 1.6-5.4, p<0.001) subgroups. The DeltaHR was a significant univariate predictor in the overall group and no-BB subgroup only. Multivariate Cox regression analysis revealed HRR(1) was the strongest prognostic marker (chi-square: 39.9, p<0.001). The VE/VCO(2) slope (residual chi-square: 21.8, p<0.001) and LVEF (residual chi-square: 9.6, p=0.002) were also retained in the regression. CONCLUSIONS These results indicate that HRR maintains prognostic value in HF irrespective of BB use. The routine inclusion of HRR in the prognostic assessment of patients with HF may be warranted.

The partial pressure of resting end-tidal carbon dioxide predicts major cardiac events in patients with systolic heart failure

BACKGROUND The resting partial pressure of end-tidal carbon dioxide (Petco2) has been shown to reflect cardiac performance in acute care settings in patients with heart failure (HF). The purpose of the present study was to compare the prognostic ability of the partial pressure of Petco2 at rest to other commonly collected resting variables in patients with systolic HF. METHODS A total of 353 patients (mean age 58.6+/-13.7, 72% male) with systolic HF were included in this study. All patients underwent cardiopulmonary exercise testing where New York Heart Association (NYHA) class, resting Petco2, peak oxygen consumption, and the minute ventilation/carbon dioxide production slope were determined. Subjects were then followed for major cardiac events (mortality, left ventricular assist device implantation implantation, urgent heart transplantation). RESULTS There were 104 major cardiac events during the 23.6+/-17.0-month tracking period. Multivariate Cox regression analysis revealed NYHA class (chi2 28.7, P<.001), left ventricular ejection fraction (residual chi2 21.7, P<.001), and resting Petco2 (residual chi2 14.1, P<.001) were all prognostically significant and retained in the regression. In a separate Cox regression analysis, left ventricular ejection fraction (residual chi2 8.8, P=.003), NYHA class (residual chi2 7.7, P=.005), and resting Petco2 (residual chi2 5.7, P=.02) added prognostic value to the minute ventilation/carbon dioxide production slope (chi2 26.0, P<.001). CONCLUSION Resting Petco2 can be noninvasively collected from subjects in a short period, at a low cost, and with no risk or discomfort to the patient. Given the prognostic value demonstrated in the present study, the clinical assessment of resting Petco2 in the HF population may be warranted.

The Lowest VE/VCO2 Ratio During Exercise as a Predictor of Outcomes in Patients With Heart Failure

BACKGROUND The lowest minute ventilation (VE) and carbon dioxide production (VCO(2)) ratio during exercise has been suggested to be the most stable and reproducible marker of ventilatory efficiency in patients with heart failure (HF). However, the prognostic power of this index is unknown. METHODS AND RESULTS A total of 847 HF patients underwent cardiopulmonary exercise testing (CPX) and were followed for 3 years. The associations between the lowest VE/VCO(2) ratio, maximal oxygen uptake (peak VO(2)), the VE/VCO(2) slope, and major events (death or transplantation) were evaluated using proportional hazards analysis; adequacy of the predictive models was assessed using Akaike information criterion (AIC) weights. There were 147 major adverse events. In multivariate analysis, the lowest VE/VCO(2) ratio (higher ratio associated with greater risk) was similar to the VE/VCO(2) slope in predicting risk (hazard ratios [HR] per unit increment 2.0, 95% CI 1.1-3.4, and 2.2, 95% CI 1.3-3.7, respectively; P < .01), followed by peak VO(2) (HR 1.6, 95% CI 1.1-2.4, P=.01). Patients exhibiting abnormalities for all 3 responses had an 11.6-fold higher risk. The AIC weight for the 3 variables combined (0.94) was higher than any single response or any combination of 2. The model including all 3 responses remained the most powerful after adjustment for beta-blocker use, type of HF, and after applying different cut points for high risk. CONCLUSIONS The lowest VE/VCO(2) ratio adds to the prognostic power of conventional CPX responses in HF.

Influence of Etiology of Heart Failure on the Obesity Paradox

Several investigations have demonstrated that higher body weight, as assessed by the body mass index, is associated with improved prognosis in patients with heart failure (HF). The purpose of the present investigation was to assess the influence of HF etiology on the prognostic ability of the body mass index in a cohort undergoing cardiopulmonary exercise testing. A total of 1,160 subjects were included in the analysis. All subjects underwent cardiopulmonary exercise testing, at which the minute ventilation/carbon dioxide production slope and peak oxygen consumption were determined. In the overall group, 193 cardiac deaths occurred during a mean follow-up of 30.7 +/- 25.6 months (annual event rate 6.0%). The subjects classified as obese consistently had improved survival compared to those classified as normal weight (overall survival rate 88.0% vs <or=81.1%, p <0.001). Differences in survival according to HF etiology were observed for those classified as overweight. In the ischemic subgroup, the survival characteristics for the overweight subjects (75.5%) were similar those for subjects classified as normal weight (81.1%). The converse was true for the nonischemic subgroup, for whom the survival trends for the obese (86.4%) and overweight subjects (88.4%) were similar. The minute ventilation/carbon dioxide production slope was the strongest prognostic marker (chi-square >or=43.4, p <0.001) for both etiologies, and the body mass index added prognostic value (residual chi-square >or=4.7, p <0.05). In conclusion, these results further support the notion that obesity confers improved prognosis in patients with HF, irrespective of the HF etiology. Moreover, the body mass index appears to add predictive value during the cardiopulmonary exercise testing assessment. However, survival appears to differ according to HF etiology in subjects classified as overweight.