Patients with heart failure (HF) have evidence of chronic systemic inflammation. Whether inflammation contributes to the exercise intolerance in patients with HF is, however, not well established. We hypothesized that the levels of C-reactive protein (CRP), an established inflammatory biomarker, predict impaired cardiopulmonary exercise performance, in patients with chronic systolic HF. We measured CRP using high-sensitivity particle-enhanced immunonephelometry in 16 patients with ischemic heart disease (previous myocardial infarction) and chronic systolic HF, defined as a left ventricular ejection fraction ≤50% and New York Heart Association class II-III symptoms. All subjects with CRP >2 mg/L, reflecting systemic inflammation, underwent cardiopulmonary exercise testing using a symptom-limited ramp protocol. CRP levels predicted shorter exercise times ( R = −0.65, p = 0.006), lower oxygen consumption (VO 2 ) at the anaerobic threshold ( R = −0.66, p = 0.005), and lower peak VO 2 ( R = −0.70, p = 0.002), reflecting worse cardiovascular performance. CRP levels also significantly correlated with an elevated ventilation/carbon dioxide production slope ( R = +0.64, p = 0.008), a reduced oxygen uptake efficiency slope ( R = −0.55, p = 0.026), and reduced end-tidal CO 2 level at rest and with exercise ( R = −0.759, p = 0.001 and R = −0.739, p = 0.001, respectively), reflecting impaired gas exchange. In conclusion, the intensity of systemic inflammation, measured as CRP plasma levels, is associated with cardiopulmonary exercise performance, in patients with ischemic heart disease and chronic systolic HF. These data provide the rationale for targeted anti-inflammatory treatments in HF.
Despite the wealth of data regarding inflammation and heart failure (HF), it has not been investigated whether C-reactive protein (CRP) or other inflammatory biomarkers correlate with cardiopulmonary exercise performance in patients with HF. In healthy subjects, CRP inversely associates with cardiopulmonary fitness. In patients with acute myocardial infarction (AMI), high CRP correlates with lower exercise capacity, whether this is also true for patients with established systolic HF remains unknown. Therefore, the purpose of this study was to determine if systemic inflammation, quantified as CRP, correlates with cardiopulmonary exercise performance, quantified by cardiopulmonary exercise testing (CPX), in patients with chronic HF being enrolled in Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) clinical trial ( ClinicalTrials.gov registration NCT01327846 ).
Methods
Prospective adult patients seen in the Cardiology outpatient clinic were screened for the following inclusion criteria: (1) symptomatic stable HF defined as an impairment of functional capacity with New York Heart Association functional class II to III symptoms, (2) history of previous MI according to the universal MI criteria, (3) left ventricular ejection fraction (LVEF) ≤50% (measured by echocardiography, angiography, or nuclear study within last 6 months), and (4) evidence of systemic inflammation (CRP >2 mg/L). Patients were excluded from study with consideration based on the following criteria: (1) recent (≤3 months) changes to HF pharmacologic regimen, (2) recent (≤3 months) or planned cardiac procedures (cardiac resynchronization therapy, implantable cardioverter defibrillator, coronary revascularization, or heart valve surgery), (3) inability to perform maximal exertion during CPX (i.e., limiting angina, significant electrocardiograph changes, and orthopedic limitation), and (4) additional noncardiac exclusion criteria pertinent to their inclusion in the CANTOS clinical trial ( ClinicalTrials.gov registration NCT01327846 ). All patients completed an informed consent before study participation. The Western Institutional Review Board (Puyallup, WA) granted approval before study commencement.
All patients underwent a single symptom-limited CPX to determine cardiopulmonary exercise performance. Contraindications to exercise testing were based on established American College of Cardiology/American Heart Association Guidelines for exercise testing. All tests were physician supervised and administered by an American College of Sports Medicine registered clinical exercise physiologist. The treadmill protocol used was a conservative incremental ramping protocol wherein the speed and grade increased by approximately 0.6 estimated METs or approximately 2 ml·kg −1 ·minute −1 every 30 seconds. This treadmill protocol has been previously described and used in an HF population. Ventilatory gas analysis was performed using a VMax Encore metabolic cart (Carefusion, Yorba Linda, California) with a standard mouthpiece and nose clip setup. The metabolic cart was calibrated for volume and gas concentration before every test. Ventilatory gas analysis measurements were obtained for at least 3 minutes in the seated position before the start of exercise, continuously throughout exercise, and 2 minutes into the recovery period. Mason–Likar exercise 12-lead electrocardiography was performed continuously before, during, and after exercise. Blood pressure (BP) was monitored with a Tango + exercise blood pressure system (Suntech Medical, Morrisville, North Carolina). BP measurements were monitored during rest, exercise, and recovery.
Standard exercise test variables analyzed: total exercise time (TET), chronotropic index (CI), BP index, heart rate recovery 1 minute postexercise (HRR 1 ), subjective rating of perceived exertion, rating of perceived dyspnea, and anginal symptoms. CPX variables analyzed included: peak VO 2 , percent-predicted (% predicted) peak VO 2 , METs, ventilatory anaerobic threshold (VAT), peak respiratory exchange ratio (RER), the VE/VCO 2 slope, the oxygen uptake efficiency slope (OUES), peak exercise oxygen pulse (O 2 pulse), and the partial pressure of end-tidal CO 2 (P ET CO 2 ) at rest and highest level during exercise.
TET was defined as the total treadmill duration in minutes and seconds. CI was defined as heart rate reserve (peak heart rate minus heart rate at rest) divided by the VO 2 reserve (peak VO 2 minus VO 2 at rest). CI ratio was determined by dividing observed CI by predicted CI. BP index was defined as systolic blood pressure reserve (peak BP minus BP at rest) divided by MET reserve (peak METs minus 1). HRR 1 was defined as peak heart rate minus heart rate at rest at 1-minute after exercise during active recovery.
Peak VO 2 was defined as the highest 10-second interval average obtained from breath-by-breath measurements of VO 2 during the last 30 seconds of exercise. In addition, % predicted normal values were reported using the reference values proposed by Wasserman et al. VAT was defined using the ventilatory equivalents method. Peak RER was the ratio of VCO 2 /VO 2 corresponding to the peak VO 2 at the end of exercise. The VE/VCO 2 slope was the linear regression value (y = mx + b, where m = slope) of the relations between VE and VCO 2 during exercise. Slope analysis was based on 10-second interval averages for VE and VCO 2 throughout the entire exercise period. The OUES was determined from the linear relation of VO 2 versus the logarithmic transformation of VE during exercise, that is, VO 2 = a·log 10 VE + b, where “a” is the OUES and “b” is the intercept. Calculation of OUES was based on 10-second interval averages for VE and absolute VO 2 (liters·minute) throughout the entire exercise period. Peak O 2 pulse was calculated as peak VO 2 divided by peak heart rate. Percentage predicted peak O 2 pulse was calculated as the percentage of predicted peak O 2 pulse. Resting P ET CO 2 measurements were based on the average value of at least 2 minutes of pre-exercise data. Exercise P ET CO 2 measurements were recorded at the highest value obtained during exercise.
All patients underwent a single transthoracic Doppler echocardiographic study to measure LVEF, using volumetric analysis for 2 perpendicular apical views, and the ratio of transmitral early diastolic velocity (E) to the mitral annulus early diastolic velocity at tissue Doppler (E′) averaging the septal and lateral mitral annulus, as a measure of diastolic filling.
The patients were assessed for systemic inflammation, defined as plasma high-sensitivity CRP levels >2 mg/L, using an automated high-sensitivity latex-enhanced assay. Plasma samples were obtained at rest, before exercise testing, and processed on the same day.
Continuous variables were reported with median and interquartile range values for potential deviation from a Gaussian distribution. Discrete variables are reported as a number and percent (%). Spearman correlation coefficients were used to assess correlations between CRP and CPX variables. Significance was set at a p value of <0.05. SPSS version 22 software (IBM, New York) was used for statistical analysis. No a priori sample size or power calculations were performed for this study.
Results
Table 1 describes the individual clinical characteristics of the patients: 14 (88%) were men, median age was 55 years, previous MI had occurred at a median of 46 months before assessment. Hypertension, obesity, and diabetes were highly prevalent ( Supplementary Table 1 ). All patients were symptomatic for HF, New York Heart Association class was 2.25 (2.0 to 2.5). The use of HF medications is also listed in Supplementary Table 1 . CRP levels ranged from 3.1 to 15.0 mg/L (median of 5.4 mg/L). Echocardiography data were available and of sufficient quality in 12 patients (75%), whereas acoustic windows were inadequate for precise cardiac measurements in 4 ( Table 1 and Supplementary Table 2 ). Left ventricular systolic function was overall mildly-to-moderately reduced with an LVEF of 42% (37% to 48%).
| Subject | Age (years) | Gender | Race | Time since MI (months) | BMI (kg/m 2 ) | CRP (mg/L) | Peak VO 2 (ml.kg.min) | %Pred. VO 2 | VAT (ml.kg.min) | VAT %Pred.VO 2 | VE/VCO 2 Slope | OUES | PetCO 2 (mmHg) | PetCO 2 (mmHg) | Exercise Time (minutes) | LVEF (%) | E/E’ |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| #1 | 43 | M | C | 69 | 43 | 5.8 | 15.7 | 41 | 12.2 | 32 | 23.1 | 3.02 | 39.4 | 54.2 | 8.4 | 38 | 12.6 |
| #2 | 44 | M | HA | 57 | 29 | 3.0 | 29.2 | 77 | 22.6 | 59 | 21.6 | 3.80 | 49.2 | 57.1 | 15.2 | 40 | 8.2 |
| #3 | 47 | M | C | 130 | 37 | 21.1 | 14.3 | 39 | 10.5 | 28 | 38 | 2.25 | 28.9 | 32.3 | 6.4 | 44 | 19.5 |
| #4 | 52 | M | AA | 99 | 25 | 4.4 | 20.0 | 57 | 14.2 | 41 | 29.1 | 2.11 | 33.4 | 44.1 | 9.1 | ||
| #5 | 52 | F | AA | 3 | 40 | 18.2 | 9.0 | 34 | 7.0 | 27 | 43.4 | 1.61 | 30.7 | 33.4 | 3.3 | 33 | 21.6 |
| #6 | 53 | M | C | 34 | 35 | 3.0 | 22.4 | 65 | 13.1 | 38 | 25.6 | 2.85 | 40.3 | 49.8 | 9.3 | 50 | 7.7 |
| #7 | 53 | M | AA | 138 | 29 | 2.0 | 29.8 | 87 | 21.8 | 63 | 26.1 | 4.20 | 43.0 | 49.2 | 12.0 | 40 | 12.0 |
| #8 | 54 | M | AA | 1 | 36 | 7.4 | 22.6 | 66 | 13.6 | 40 | 25.2 | 2.92 | 38.3 | 48.9 | 10.5 | ||
| #9 | 56 | F | C | 5 | 33 | 17.3 | 13.3 | 56 | 11.3 | 47 | 30.8 | 1.81 | 30.4 | 38.1 | 6.0 | 49 | 11.4 |
| #10 | 58 | M | C | 133 | 36 | 7.9 | 17.5 | 54 | 15.4 | 48 | 31 | 2.54 | 32.0 | 38.8 | 6.5 | ||
| #11 | 59 | M | AA | 188 | 40 | 3.3 | 16.1 | 50 | 9.1 | 28 | 27.4 | 2.36 | 44.8 | 52.1 | 6.2 | ||
| #12 | 61 | M | C | 117 | 25 | 2.8 | 26.1 | 84 | 17.9 | 58 | 25.9 | 2.40 | 46.5 | 55.2 | 10.4 | 47 | 7.7 |
| #13 | 61 | M | AA | 19 | 28 | 19.0 | 20.9 | 67 | 12.0 | 39 | 33.5 | 1.93 | 35.1 | 40.9 | 7.5 | 35 | 19.5 |
| #14 | 62 | M | C | 23 | 35 | 4.2 | 24.4 | 79 | 18.3 | 60 | 28.9 | 2.71 | 36.1 | 44.7 | 10.4 | 50 | 9.9 |
| #15 | 65 | M | C | 21 | 24 | 5.8 | 13.8 | 47 | 12.3 | 42 | 54.8 | 1.15 | 24.9 | 27.0 | 7.2 | 14 | 24.8 |
| #16 | 68 | M | C | 1 | 25 | 4.9 | 18.4 | 65 | 15.0 | 53 | 29.3 | 2.00 | 32.8 | 43.3 | 11.0 | 47 | 8.7 |
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