Daniel Bensimhon

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.

Reproducibility of Peak Oxygen Uptake and Other Cardiopulmonary Exercise Testing Parameters in Patients With Heart Failure (from the Heart Failure and A Controlled Trial Investigating Outcomes of exercise traiNing)

Peak oxygen uptake (pVo2) is an important parameter in assessing the functional capacity and prognosis of patients with heart failure. In heart failure trials, change in pVo2 was often used to assess the effectiveness of an intervention. However, the within-subject variability of pVo2 on serial testing may limit its usefulness. This study was designed to evaluate the within-subject variability of pVo2 over 2 baseline cardiopulmonary exercise tests. As a substudy of the HF-ACTION trial, 398 subjects (73% men, 27% women; mean age 59 years) with heart failure and left ventricular ejection fraction < or =35% underwent 2 baseline cardiopulmonary exercise tests within 14 days. Mean pVo2 was unchanged from test 1 to test 2 (15.16 +/- 4.97 vs 15.18 +/- 4.97 ml/kg/min; p = 0.78). However, mean within-subject absolute change was 1.3 ml/kg/min (10th, 90th percentiles 0.1, 3.0), with 46% of subjects increasing and 48% decreasing on the second test. Other parameters, including the ventilation-to-carbon-dioxide production slope and Vo2 at ventilatory threshold, also showed significant within-subject variation with minimal mean differences between tests. In conclusion, pVo2 showed substantial within-subject variability in patients with heart failure and should be taken into account in clinical applications. However, on repeated baseline cardiopulmonary exercise tests, there appears to be no familiarization effect for Vo2 in patients with HF. Therefore, in multicenter trials, there is no need to perform >1 baseline cardiopulmonary exercise test.

Worsening Depressive Symptoms Are Associated With Adverse Clinical Outcomes in Patients With Heart Failure

OBJECTIVES The purpose of this study was to assess the impact of changes in symptoms of depression over a 1-year period on subsequent clinical outcomes in heart failure (HF) patients. BACKGROUND Emerging evidence shows that clinical depression, which is prevalent among patients with HF, is associated with a poor prognosis. However, it is uncertain how changes in depression symptoms over time may relate to clinical outcomes. METHODS One-hundred forty-seven HF outpatients with ejection fraction of less than 40% were assessed for depressive symptoms using the Beck Depression Inventory (BDI) at baseline and again 1 year later. Cox proportional hazards regression analyses, controlling for established risk factors, were used to evaluate how changes in depressive symptoms were related to a combined primary end point of death or cardiovascular hospitalization over a median follow-up period of 5 years (with a range of 4 to 7 years and no losses to follow-up). RESULTS The 1-year change in symptoms of depression, as indicated by higher BDI scores over a 1-year interval (1-point BDI change hazard ratio [HR]: 1.07, 95% confidence interval [CI]: 1.02 to 1.12, p = 0.007), was associated with death or cardiovascular hospitalization after controlling for baseline depression (baseline BDI HR: 1.1, 95% CI: 1.06 to 1.14, p < 0.001) and established risk factors, including HF cause, age, ejection fraction, plasma N-terminal pro-B-type natriuretic peptide level, and prior hospitalizations. CONCLUSIONS Worsening symptoms of depression are associated with a poorer prognosis in HF patients. Routine assessment of symptoms of depression in HF patients may help to guide appropriate medical management of these patients who are at increased risk for adverse clinical outcomes.

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.

Increased levels of apoptosis in gastrocnemius skeletal muscle in patients with peripheral arterial disease

Intermittent claudication (IC) is the major clinical manifestation of peripheral arterial disease (PAD). Apoptosis has been linked to skeletal muscle pathophysiology in other chronic diseases such as congestive heart failure. This study tested the hypothesis that there would be increased levels of apoptosis in the skeletal muscle of patients with PAD compared with control individuals. In total, 26 individuals with PAD and 28 age-appropriate controls underwent studies of peak oxygen consumption (peak VO2) and a gastrocnemius muscle biopsy in the most symptomatic leg. Muscle biopsies were analyzed for apoptosis and caspase-3 activity. Patients with PAD had a reduced peak VO2 compared with controls. Apoptosis was increased in those with PAD compared with age-appropriate controls (3.83% ± 2.6 vs 1.53% ± 0.96; p < 0.001). In conclusion, PAD is associated with increased levels of apoptosis in the peripheral skeletal muscle. Further study is required to ascertain whether apoptosis plays a role in decreased functional capacity.

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.