Joshua Abella

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.

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.

Comparison of the chronotropic response to exercise and heart rate recovery in predicting cardiovascular mortality.

Background Both an impaired capacity to increase heart rate during exercise testing (chronotropic incompetence), and a slowed rate of recovery following exercise (heart rate recovery) have been shown to be associated with all-cause mortality. It is, however, unknown which of these responses more powerfully predicts risk, and few data are available on their association with cardiovascular mortality or how they are influenced by β-blockade. Methods Routine symptom-limited exercise treadmill tests performed on 1910 male veterans at the Palo Alto Veterans Affairs Medical Center from 1992 to 2002 were analyzed. Heart rate was determined each minute during exercise and recovery. Chronotropic incompetence was defined as the inability to achieve ≥80% of heart rate reserve, using a population-specific equation for age-predicted maximal heart rate. An abnormal heart rate recovery was considered to be a decrease of <22 beats/min at 2min in recovery. Cox proportional hazards analyses including pretest clinical data, chronotropic incompetence, heart rate recovery, the Duke Treadmill Score (abnormal defined as <4), and other exercise test responses were performed to determine their association with cardiovascular mortality. Results Over a mean follow-up of 5.1 ± 2.1 years, there were 70 deaths from cardiovascular causes. Both abnormal heart rate recovery and chronotropic incompetence were associated with higher cardiovascular mortality, a lower exercise capacity, and more frequent occurrence of angina during exercise. Both heart rate recovery and chronotropic incompetence were stronger predictors of risk than pretest clinical data and traditional risk markers. Multivariately, chronotropic incompetence was similar to the Duke Treadmill Score for predicting cardiovascular mortality, and was a stronger predictor than heart rate recovery [hazard ratios 3.0 (95% confidence interval 1.9–4.9), 2.8 (95% confidence interval 1.7–4.8), and 2.0 (95% confidence interval 1.1–3.5) for abnormal Duke Treadmill Score, chronotropic incompetence, and abnormal heart rate recovery, respectively]. Having both chronotropic incompetence and abnormal heart rate recovery strongly predicted cardiovascular death, resulting in a relative risk of 4.2 compared with both responses being normal. Beta-blockade had minimal impact on the prognostic power of chronotropic incompetence and heart rate recovery. Conclusion Both chronotropic incompetence and heart rate recovery predict cardiovascular mortality in patients referred for exercise testing for clinical reasons. Chronotropic incompetence was a stronger predictor of cardiovascular mortality than heart rate recovery, but risk was most powerfully stratified by these two responses together. The simple application of heart rate provides powerful risk stratification for cardiovascular mortality from the exercise test, and should be routinely included in the test report.

Exercise Capacity and All-Cause Mortality in African American and Caucasian Men With Type 2 Diabetes

OBJECTIVE The purpose of this study was to assess the association between exercise capacity and mortality in African Americans and Caucasians with type 2 diabetes and to explore racial differences regarding this relationship. RESEARCH DESIGN AND METHODS African American (n = 1,703; aged 60 ± 10 years) and Caucasian (n = 1,445; aged 62 ± 10 years) men with type 2 diabetes completed a maximal exercise test between 1986 and 2007 at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, California. Three fitness categories were established (low-, moderate-, and high-fit) based on peak METs achieved. Subjects were followed for all-cause mortality for 7.3 ± 4.7 years. RESULTS The adjusted mortality risk was 23% higher in African Americans than in Caucasians (hazard ratio 1.23 [95% CI 1.1–1.4]). A graded reduction in mortality risk was noted with increased exercise capacity for both races. There was a significant interaction between race and METs (P < 0.001) and among race and fitness categories (P < 0.001). The association was stronger for Caucasians. Each 1-MET increase in exercise capacity yielded a 19% lower risk for Caucasians and 14% for African Americans (P < 0.001). Similarly, the risk was 43% lower (0.57 [0.44–0.73]) for moderate-fit and 67% lower (0.33 [0.22–0.48]) for high-fit Caucasians. The comparable reductions in African Americans were 34% (0.66 [0.55–0.80]) and 46% (0.54 [0.39–0.73]), respectively. CONCLUSIONS Exercise capacity is a strong predictor of all-cause mortality in African American and Caucasian men with type 2 diabetes. The exercise capacity-related reduction in mortality appears to be stronger and more graded for Caucasians than for African Americans.

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.

Fitness and Fatness as Mortality Predictors in Healthy Older Men: The Veterans Exercise Testing Study

BACKGROUND Low body mass index (BMI) and low cardiorespiratory fitness (CRF) are independently associated with increased mortality in the elderly. However, interactions among BMI, CRF, and mortality in older persons have not been adequately explored. METHODS Hazard ratios (HRs) were calculated for predetermined strata of BMI and CRF. Independent and joint associations of CRF, BMI, and all-cause mortality were assessed by Cox proportional hazards analyses in a prospective cohort of 981 healthy men aged at least 65 years (mean age [+/-SD], 71 [+/-5] years; range, 65-88 years) referred for exercise testing during 1987-2003. RESULTS During a mean follow-up of 6.9 +/- 4.4 years, a total of 208 patients died. Multivariate relative risks (95% confidence interval [CI]) of mortality across BMI groups of <20.0, 20.0-25.0, 25.0-29.9, 30.0-34.9, and > or =35.0 were 2.51 (1.26-4.98), 1.0 (reference), 0.66 (0.48-0.90), 0.50 (0.31-0.78), and 0.44 (0.20-0.97), respectively, and across CRF groups of <5.0, 5.0-8.0, and >8.0 metabolic equivalents were 1.0 (reference), 0.56 (0.40-0.78), and 0.39 (0.26-0.58), respectively. In a separate analysis of within-strata CRF according to BMI grouping, the lowest mortality risk was observed in obese men with high fitness (HR [95% CI] 0.26 [0.10-0.69]; p = .007). CONCLUSIONS In this cohort of elderly male veterans, we observed independent and joint inverse relations of BMI and CRF to mortality. This warrants further investigation of fitness, fatness, and mortality interactions in older persons.

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.

Maximal exercise oxygen pulse as a predictor of mortality among male veterans referred for exercise testing

Background Maximal oxygen pulse (O2 pulse) mirrors the stroke volume response to exercise, and should therefore be a strong predictor of mortality. Limited and conflicting data are, however, available on this issue. Methods Nine hundred forty-eight participants, classified as those with cardiopulmonary disease (CPD) and those without (non-CPD), underwent cardiopulmonary exercise testing (CPX) for clinical reasons between 1993 and 2003. The ability of maximal O2 pulse and maximal oxygen uptake (peak VO2) to predict mortality was investigated using proportional hazards and Akaike information criterion analyses. All-cause mortality was the endpoint. Results Over a mean follow-up of 6.3 ± 3.2 years, there were 126 deaths. Maximal O2 pulse, expressed in either absolute or relative to age-predicted terms, and peak VO2 were significant and independent predictors of mortality in those with and without CPD (P < 0.04). Akaike information criterion analysis revealed that the model including both maximal O2 pulse and peak VO2 had the highest accuracy for predicting mortality. The optimal cut-points for O2 pulse and peak VO2 (< 12; ≥ 12 ml/beat and < 16; ≥ 16 ml/(kg · min) respectively) were established by the area under the receiver-operating-characteristic curve. The relative risks of mortality were 3.4 and 2.2 (CPD and non-CPD, respectively) among participants with both maximal O2 pulse and peak VO2 responses below these cut-points compared with participants with both responses above these cut-points. Conclusion These results indicate that maximal O2 pulse is a significant predictor of mortality in patients with and without CPD. The addition of absolute and relative O2 pulse data provides complementary information for risk-stratifying heterogeneous participants referred for CPX and should be routinely included in the CPX report.

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.