Background: Higher cardiorespiratory fitness (CRF) is associated with lower morbidity and mortality in patients with coronary heart disease (CHD). The mechanisms for this are not fully understood. A more favourable cardiometabolic risk factor profile may be responsible; however, few studies have comprehensively evaluated cardiometabolic risk factors in relation to CRF amongst patients with CHD. We aimed to explore differences in cardiometabolic risk and 5-year all-cause mortality risk in patients with CHD who have low, moderate, and high levels of CRF. Methods: Patients with CHD underwent maximal cardiopulmonary exercise testing, echocardiogram, carotid intima-media thickness measurement, spirometry, and dual X-ray absorptiometry assessment. Full blood count, biochemical lipid profiles, high-sensitivity (hs) C-reactive protein, and NT-proBNP were analysed. Patients were defined as having low, moderate, or high CRF based on established prognostic thresholds. Results: Seventy patients with CHD (age 63.1 ± 10.0 years, 86% male) were recruited. Patients with low CRF had a lower ventilatory anaerobic threshold, peak oxygen pulse, post-exercise heart rate recovery, and poor ventilatory efficiency. The low CRF group also had higher NT pro-BNP, hs-CRP, non-fasting glucose concentrations, and lower haemoglobin and haematocrit. Five-year mortality risk (CALIBER risk score) was also greatest in the lowest CRF group (14.9%). Conclusions: Practitioners should interpret low CRF as an important clinical risk factor associated with adverse cardiometabolic health and poor prognosis, study registry; www.researchregistry.com. Keywords: Coronary Heart Disease, Cardiac Rehabilitation, Cardiometabolic Health, Exercise Training, Atherosclerosis, VO , Maximal Cardiopulmonary Exercise Testing, CALIBER 5-year risk 2peak Key Points with the lowest cardiorespiratory fitness, even when left ventricular ejection fraction is preserved. 1. Low cardiorespiratory fitness is associated with the Longer-term or higher intensity exercise-based car- poorest cardiometabolic health in patients with diac rehabilitation programmes that closely monitor coronary heart disease. cardiovascular risk factors may be warranted for 2. Five-year risk of all-cause death and NT-proBNP coronary heart disease patients who have low car- are highest amongst coronary heart disease patients diorespiratory fitness. Background * Correspondence: firstname.lastname@example.org Cardiorespiratory fitness (CRF) or VO predicts 2peak Centre for Sport and Exercise Science, Sheffield Hallam University, Collegiate Hall, Collegiate Crescent, Sheffield S10 2BP, UK all-cause and cardiovascular (CV) mortality in patients Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Nichols et al. Sports Medicine - Open (2018) 4:22 Page 2 of 11 with coronary heart disease (CHD) [1–3]. We have angina, myocardial infarction (MI), coronary artery by- shown that in patients with CHD, low CRF confers the pass graft (CABG) surgery, or elective percutaneous cor- highest mortality risk (54%) over a 14-year period when onary intervention (PCI). After giving verbal consent, compared to those categorised as having moderate (31%) patients were invited for assessment at Academic Cardi- or high CRF [17%] . Improvements in CRF resulting ology, Castle Hill Hospital, Kingston-Upon-Hull, United from exercise-based cardiac rehabilitation (CR) may re- Kingdom, where written informed consent was obtained. duce mortality in patients who have low CRF [4–6]. Whilst higher CRF is a strong predictor of better sur- Resting Haemodynamics, Anthropometry, and Body vival outcomes, the mechanisms responsible for this asso- Composition ciation are not fully understood. Few studies have Resting heart rate (HR) was determined at the end of comprehensively profiled the cardiometabolic health status 15 min, semi-supine rest using a 12-lead ECG (GE of patients with CHD in relation to established CRF cat- Healthcare, Buckinghamshire, UK). Left arm brachial egories. Higher all-cause mortality in patients with CHD blood pressure was recorded using an ECG-gated auto- may not be entirely attributable to older age, cardiovascu- mated blood pressure (BP) cuff (Tango, SunTech lar disease (CVD) severity, and more comorbidities . Medical, Eynsham, UK). Unidentified and potentially treatable cardiometabolic risk Stature (cm) was measured using a Leicester Height factors may cause the divergence in mortality rates ob- Measure (SECA, Birmingham, UK) with patients stand- served between patients with high and low CRF. ing, without footwear, in the Frankfort plane with their Biomarkers of cardiac dysfunction, inflammation, car- heels and head positioned to the back of the stadi- diac autonomic function, arterial plaque status, renal ometer. Waist circumference measurements were taken function, blood oxygen carrying capacity, and metabolic 1 cm above the iliac crest , and hip measurements control have received little attention in relation to CRF were taken from the widest aspect of the buttocks using in patients with CHD. Where limited data does exist, an inflexible tape measure. Both measurements were re- CRF is often reported as estimated metabolic equiva- corded in centimetre, and a ratio of the two was calcu- lents (METS) from treadmill or cycle ergometer work- lated to determine waist to hip circumference ratio . loads [2, 4, 6]. Fitness estimation may be inaccurate in Body composition was analysed using dual X-ray patients with CHD, could result in individual patients absorptometry [DXA] (Lunar iDXA, GE Healthcare, being inappropriately assigned to a specific CRF cat- Buckinghamshire, UK). Total body mass (kg), lean body egory and, attenuate any prognostic signal . The as- mass (kg), total fat (%), android fat (%), and android sociation between cardiometabolic health and CRF gynoid ratio were determined using the Lunar iDXA’s in- should be investigated using ‘gold-standard’ maximal tegrated software. DXA-derived total body mass was − 2 cardiopulmonary exercise testing (CPET). used to determine body mass index (BMI; kg.m ). This cross-sectional investigation aimed to assess dif- ferences in CV and cardiometabolic health amongst pa- Echocardiogram tients with CHD when characterised as have low, Standard 2D, M-mode echocardiogram techniques were moderate, or high levels of CRF. We also investigated used to determine left ventricular (LV) function. LV ejection differences in estimated 5-year risk of death using the fraction (LVEF) was calculated using the Simpson’smethod validated CALIBER composite scoring system . from measurements of end-diastolic and end-systolic vol- umes on apical 4-chamber and 2-chamber 2D views follow- Methods ing the guidelines of Schiller and colleagues . LV systolic Study Design dysfunction was diagnosed if LVEF was ≤ 45%. Data for this study were taken from the Cardiovascular and cardiorespiratory Adaptations to Routine Carotid Intima-Media Thickness and Carotid Plaque Exercise-based Cardiac Rehabilitation study (CARE CR). Measurement Ethical approval for the study was given by the Humber Carotid intima-media thickness (C-IMT) and carotid Bridge NHS Research Ethics Committee-Yorkshire and plaque measurements were obtained using the Panaso- the Humber (12/YH/0278). The study is registered with nic CardioHealth Station (Panasonic Biomedical Sales www.researchregistry.com (researchregistry3548). All Europe BV, Leicestershire, UK) which has low measure- procedures were conducted in accordance with the eth- ment variability [13, 14]. Measurements were taken ical standards outlined in the 1964 Helsinki declaration using previously outlined methods [10, 13] from a 1 cm and its later amendments. segment of the common carotid artery (CCA) located The methodology for this study has been reported 1 cm proximally from the carotid bifurcation. Measure- elsewhere . In brief, patients were recruited following ments from the right and left CCA were taken in the a recent hospital admission and referral to CR for stable longitudinal plane at anterior (right CCA 150°; left CCA Nichols et al. Sports Medicine - Open (2018) 4:22 Page 3 of 11 210°), lateral (right CCA 120°; 230°), and posterior (right the V-slope method  by two independent investi- CCA 90°; left CCA 270°) angles, relative to ground. Each gators. Where agreement on VAT scores was not C-IMT measurement was determined from the average met, the results were discussed with a third inde- of 24 digital distance markers automatically placed be- pendent investigator and a consensus was reached. tween the intimal and medial boundaries and reported The VAT was determined using the average of the to three decimal places. Carotid artery plaques were middle 5 of 7 consecutive breaths (excluding the measured in the longitudinal plane. The largest plaque highest and lowest measures) and reported standar- was taken as the representative measure of the patient’s dised to patient body mass (ml/kg/min). The oxygen carotid plaque status and reported as being either < uptake efficiency slope (OUES), VE/VCO slope, and 1.0 mm, ≥ 1.0 to < 3.0 mm or ≥ 3.00 mm. oxygen pulse (VO /HR) were calculated as previously described . Self-reported weekly physical activity Blood Samples levels were obtained by asking patients if they partic- Blood samples were taken from a vein at the antecubital ipated in either 150 min of moderate physical activ- fossa and collected in ethylenediaminetetraacetic acid ity, 75 min of vigorous physical activity, or both. (EDTA), potassium oxalate, and serum separating tubes (SST). Full blood count, (haematocrit, haemoglobin, and Determination of Cardiorespiratory Fitness Categories neutrophil and lymphocyte count) and estimated glom- Patients were categorised into three groups based on erular filtration rate (eGFR) were analysed on the day of their VO . We converted VO into metabolic 2peak 2peak collection using a registered National Health Service equivalents (METs) by dividing by 1 MET (estimated to (NHS) pathology lab (Castle Hill Hospital, Hull, United be equivalent to a VO of 3.5 ml/kg/min) to allow for Kingdom). A further EDTA and potassium oxalate tube easier comparisons with other studies. Low CRF was de- were placed in a refrigerated (4 °C) centrifuge at fined as a peak MET value of < 5 for men and < 4 for 3000 rpm, for 15 min immediately after the blood draw. women; high CRF was defined as peak MET > 7 for men Samples collected in SST tubes were allowed to clot for and > 6 for women. These thresholds were based on pre- 30 min prior to being centrifuged under the same viously published prognostic thresholds [4–6, 22, 23]. conditions. The ABX Pentra 400 biochemistry auto analyser Prognosis—CALIBER 5-year Risk Score (Horiba, Montpellier, France) was used to analyse serum A 5-year risk of all-cause mortality was calculated for triglycerides, total cholesterol, high-density lipoprotein each patient using the comprehensive online (www.cali- cholesterol (HDL), plasma glucose, and high-sensitivity berresearch.org/model) CALIBER 5-year risk score . C-reactive protein (hs-CRP) in duplicate. Calibration This model does not include any CRF measurements in and quality controls were conducted in accordance with its calculation. A full list of included variables can be manufacturer’s guidelines. Low-density lipoprotein found in Table 1. Five-year risk of all-cause mortality was (LDL) was estimated using the Friedewald equation . reported as a percentage to one decimal place. Cardiopulmonary Exercise Testing and Assessment of Statistical Analysis Physical Activity Statistical analysis was performed using SPSS version 22 After 3 min of seated rest, CPET was conducted follow- (IBM, New York, USA). The Shapiro-Wilk test and his- ing the modified Bruce treadmill protocol (GE Health- tograms were used to assess normality. Categorical data care, Buckinghamshire, UK)  in accordance with are reported as percentages. Continuous normally dis- established guidelines [17–20]. A 12-lead ECG was mon- tributed variables are displayed as mean with 95% confi- itored continuously throughout the test. An ECG-gated dence intervals (95% CI) or standard deviation (±) where automated BP measurement was recorded at the start of specified. One-way analysis of variance (ANOVA), CPET and at the second minute of a test stage until the one-way analysis of covariance (ANCOVA), and end of the test. RPE scores were recorded at peak exer- chi-squared analysis were used to assess differences be- cise. HR was recorded at 1, 2, 3, and 6 min during the tween CRF groups. The only covariate considered in passive seated recovery period. analysis was age as sex was used in assigning patients to Breath-by-breath gas exchange data were collected their CRF category. using an Oxycon Pro metabolic cart (Jaeger, Statistical significance was set at p < 0.05. Partial eta Hoechburg, Germany). VO was defined as the squared (η ) effect sizes were used to report the magni- 2peak p mean VO (ml) over the last 30 s of the CPET. tude of group differences. Effect sizes of 0.01, 0.06, and VO was adjusted for both body mass and lean 0.14 denoted small, moderate, and large effect sizes, re- 2peak (DXA-derived) body mass (ml/kg/min). The ventila- spectively . Pearson correlations were used to assess tory anaerobic threshold (VAT) was determined using the strength of the relationship between CRF category Nichols et al. Sports Medicine - Open (2018) 4:22 Page 4 of 11 Table 1 Variables Included in the CALIBER 5-Year Risk Score three groups with the exception of diuretics which were more commonly prescribed to patients in the low CRF Categorical Variables Continuous Variables group (p = 0.001). Sex Age (years) Belongs to most deprived quintile Total cholesterol (mmol/L) Cardiorespiratory Fitness and Physical Activity CAD diagnosis and severity HDL (mmol/L) Cardiorespiratory fitness and physical activity-related Interventions (last 6 months) Heart rate (beats per minute) variables are shown in Table 4. Differences in VO 2peak Smoking status Creatinine (micromol/L) standardised to lean body mass, VAT, VO /HR, and ex- Hypertension/BP lowering medication White cell count (10^9/L) ercise test duration were observed across all groups. Compared to patients with high CRF, VE/VCO slope Diabetes Haemoglobin (g/dl) 2 and OUES were both higher amongst patients in the Heart failure moderate and low CRF groups. Mean LVEF was not dif- Peripheral arterial disease ferent across the groups and was not significantly corre- Atrial fibrillation lated with peak METs (r = 0.147; p = 0.224). One patient Stroke in both the low and moderate CRF groups had a LVEF Chronic renal disease < 40%. Compared to patients with high and moderate CRF, patients with low CRF had the most impaired COPD 1-min HR recovery, an indicator of cardiac autonomic Cancer function. The proportion of patients who reported par- Chronic liver disease ticipating in either 150 min of moderate (p = 0.011) or Depression 75 min of vigorous physical activity per week was higher Anxiety in the high CRF group. CAD coronary artery disease, BP blood pressure, COPD chronic obstructive pulmonary disease, HDL high-density lipoprotein Blood Biomarkers and Cardiovascular Risk Results of blood biochemical analyses are displayed in and CALIBER 5-year risk of death. An r value of < 0.25, Table 5. NT-proBNP was inversely associated with CRF 0.26 to 0.50, 0.51 to 0.75, and, > 0.75 were considered (r = -0.414) and was highest amongst patients with low weak, moderate, fair, and strong associations, respect- CRF. Four (40%) patients with low CRF had an ively . NT-proBNP > 400 pg/ml compared to eight (25%) and one (4%) in the moderate and high CRF groups. One Results patient in the low CRF group without previously diag- Cohort Characteristics nosed chronic heart failure (CHF) had an NT-proBNP Seventy patients were recruited. Sixteen (23%) patients result > 2000 pg/ml with a mildly reduced LVEF (45%), had sustained an ST-elevation myocardial infarction sinus rhythm, and with an eGFR of 73 mL/min/1.73 m . (STEMI), 22 (31%) had sustained a non-STEMI, and 19 Lipid profiles did not differ between groups. Non-fasting (27%) had undergone elective PCI. Seven patients (10%) plasma glucose concentrations in the low CRF group were medically managed for stable angina, and six (9%) were higher than the moderate CRF group (p = 0.008). had undergone CABG. The mean age of the cohort was hs-CRP was also highest in the low CRF group. Haem- . − 2 63.1 ± 10.0 years (BMI 29.2 kg m ± 4.0; 86% male). The atocrit and haemoglobin differed between all groups. mean LVEF was 55.0 ± 6.9%. The median time from car- diac event to consent was 54 days (range 22 to 220). 94% Carotid Intima-Media Thickness of patients were seen within 90 days. A moderate inverse correlation between left-sided Twenty-eight (40%), 32 (46%), and 10 (14%) of patients C-IMT measurements and CRF was observed (r = − 0.382; were defined as having high, moderate, and low levels of p = 0.001) with larger measurements seen in the low CRF, respectively. CRF group characteristics are shown (0.926; 95% CI 0.797, 1.054; p = 0.002) and moderate CRF in Table 2. Patients with low CRF were older (p < 0.001) groups (0.827; 95% CI 0.755, 0.898; p =0.011) compared and had a lower lean body mass than patients with to the high CRF group [0.689; 95% CI 0.612, 0.765] (Fig. 1). moderate (p = 0.029) and high CRF (p = 0.002). Com- There was no significant correlation between right sided pared to patients with high (p < 0.001) and moderate C-IMT and CRF (r = − 0.210; p = 0.080). The proportion CRF (p = 0.002), patients with low CRF also had a lower of patients with left-sided plaque score < 1 mm (Fig. 2)in- android gynoid ratio, higher resting HR (high CRF, p = creased with each CRF group (low 10%; moderate 25%; 0.004; moderate CRF, p = 0.042), and a larger propor- high 39%). The proportion of patients exhibiting large tion of patients suffering from type II diabetes (p = left-sided plaque scores (> 3 mm) decreased across 0.028). Medications (Table 3) were comparable across all each group (low 40%; moderate 16%; high 4%; p = Nichols et al. Sports Medicine - Open (2018) 4:22 Page 5 of 11 Table 2 Patient Characteristics Expressed as Mean (95% Confidence Intervals) Variable High CRF, n = 28 Mod CRF, n = 32 Low CRF, n = 10 Partial eta squared p value Sex (% male) 26 (93) 27 (84) 7 (70) 0.199 *✝ ✝ * ** Age (years) 56.3 (53.1, 59.4) 67.2 (64.3, 70.2) 69.3 (64.1, 74.5) 0.326 < 0.001 −2 BMI (kg.m ) 29.0 (27.5, 30.5) 28.9 (27.5, 30.3) 30.9 (28.3, 33.4) 0.030 0.363 Waist circumference (cm) 101.3 (97.3, 105.4) 102.6 (98.7, 106.4) 108.1 (101.4, 114.9) 0.043 0.235 Waist to hip ratio (cm) 0.96 (0.93, 0.98) 0.98 (0.95, 1.00) 0.96 (0.92, 1.01) 0.018 0.553 Android fat % 45.0 (42.0, 48.0) 48.0 (45.2, 50.8) 47.9 (42.9, 52.9) 0.034 0.316 Total fat % 35.9 (32.2, 39.6) 37.3 (33.8, 40.7) 41.1 (34.8, 47.3) 0.029 0.371 *✝ ✝ * ** Lean body mass (Kg) 55.0 (51.9, 58.1) 50.2 (47.3, 53.1) 45.3 (40.1, 50.5) 0.145 0.005 * x *x ** Android/gynoid ratio 1.31 (1.24, 1.38) 1.26 (1.20, 1.32) 1.06 (0.95, 1.17) 0.182 0.001 LVEF (%) 56.6 (54.0, 59.2) 54.3 (51.8, 56.6) 52.8 (48.5, 57.1) 0.043 0.232 * x *x ** Resting HR (bpm) 56 (52, 69) 59 (56, 63) 67 (61, 74) 0.118 0.015 Resting SBP (mmHg) 130 (122, 137) 124 (117, 131) 138 (125, 150) 0.056 0.147 Resting DBP (mmHg) 85 (80, 89) 82 (77, 86) 73 (65, 81) 0.083 0.055 FEV /FVC ratio 0.78 (0.75, 0.81) 0.75 (0.72, 0.78) 0.75 (0.70, 0.80) 0.042 0.237 Presenting diagnosis MI (%) 17 (61) 15 (47) 6 (60) 0.642 PCI (%) 8 (29) 11 (34) 1 (10) Angina (%) 2 (7) 3 (9) 2 (20) CABG (%) 1 (4) 3 (9) 1 (10) Past medical history Previous MI (%) 6 (21) 6 (19) 2 (20) 0.186 ** Type II diabetes (%) 3 (12) 6 (19) 5 (50) 0.028 Atrial fibrillation (%) 0 (0) 2 (6) 1 (10) 0.269 Smoker (%) 1 (4) 1 (3) 2 (20) 0.238 Ex-smoker (%) 16 (57) 16 (50) 7 (70) Mod moderate, BMI body mass index, LVEF left ventricular ejection fraction, HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, FEV1/FVC ratio of forced expiratory volume in 1 s to forced vital capacity, MI myocardial infarction, PCI percutaneous coronary intervention, CABG coronary artery bypass graft **Significant group effect *Significant difference between high CRF and low CRF Significant difference between high CRF and moderate CRF Significant difference between mod CRF and low CRF 0.047). Patients with moderate and low CRF had in- Statistical Adjustment for Age crementally higher proportions of patients with Differences in left-sided mean C-IMT (p = 0.274; right-sided plaque scores > 3 mm (moderate CRF η = 0.039) became non-significant following age ad- 9.4%; low CRF 30%) compared to patients in the high justment. Statistically significant differences for all CRFwho hadnoplaques >3 mm (Fig. 2; p = 0.032). other variables remained unaltered after statistical ad- justment for age. All-Cause Mortality Estimation Discussion Differences in CALIBER 5-year risk (Fig. 3) were ob- To our knowledge, this is the first study to comprehensively served between all groups. Estimated risk was highest profile the cardiometabolic and CV health status of patients in the low CRF group (14.9; 95% CI 11.4, 18.5%). The with CHD according to prognostically verified CRF categor- moderate group had a 9.7% 5-year risk of death (95% ies [4–6, 22, 23]. Patients with the lowest CRF have the CI 7.7, 11.7%) whilst high CRF was associated with low- poorest integrated cardiorespiratory function and cardio- est 5-year risk of death (3.7%; 95% CI 1.6, 5.8%). There metabolic health. Patients with low CRF may also have im- was a negative association between peak METS and paired autonomic function and worse CV disease severity. CALIBER 5-year risk score (r = − 0.538; r = 0.289; p = Low CRF was associated with the poorest CALIBER 5-year <0.001). all-cause mortality risk and ‘high risk’ status (defined as 3% Nichols et al. Sports Medicine - Open (2018) 4:22 Page 6 of 11 Table 3 Number (%) of Medications Taken by Patients Medication High CRF, n = 28 Mod CRF, n = 32 Low CRF, n =10 p value Aspirin (%) 27 (96) 31 (97) 10 (100) 0.838 Ticagrelor (%) 15 (54) 17 (53) 3 (30) 0.393 Clopidogrel (%) 10 (36) 8 (25) 3 (30) 0.665 Anti-coagulants (%) 0 (0) 1 (3) 1 (10) 0.263 Beta-blockers (%) 24 (86) 29 (91) 7 (70) 0.266 ACE-inhibitors (%) 19 (68) 16 (50) 7 (70) 0.291 Angiotensin receptor blockers (%) 0 (0) 5 (16) 1 (10) 0.096 Statins (%) 25 (89) 32 (100) 10 (100) 0.095 Diuretics (%) 1 (4) 1 (3) 5 (50) 0.001** Calcium channel blockers (%) 4 (14) 8 (25) 4 (40) 0.502 Nitrates (%) 2 (7) 3 (9) 3 (30) 0.233 ACE angiotensin converting enzyme **Significant group effect Table 4 Cardiorespiratory Fitness and Physical Activity Characteristics Expressed as Mean (95% Confidence Intervals) Variable High CRF, n = 28 Mod CRF, n = 32 Low CRF, n = 10 Partial eta squared + + + VO (ml/kg/min) 28.5 (27.3, 29.7) 20.7 (19.5, 21.8) 14.9 (12.8, 16.9) – 2peak + + + VO (L/min) 2478.2 (2333.0, 2623.5) 1749.0 (1613.1, 1884.9) 1273.8 (1030.7, 1516.8) – 2peak + + + VO -lean (ml/kg/min) 45.2 (43.4, 47.0) 34.8 (33.2, 36.5) 26.8 (23.8, 29.8) 0.670 2peak + + + VAT (ml/kg/min) 20.7 (19.3, 22.1) 14.6 (13.3, 15.9) 11.2 (8.9, 13.6) 0.494 ✝ ✝ * VE/VCO slope 30.1 (28.2, 32.1)* 37.4 (35.6, 39.2) 38.5 (35.2, 41.7) 0.354 + + + VO /HR (ml/beat) 17.0 (15.8, 18.2) 13.8 (12.7, 14.9) 11.3 (9.4, 13.3) 0.311 ✝ ✝ * OUES 2718.3 (2555.3, 2881.3)* 1963.5 (1811.1, 2116.0) 1699.0 (1426.2, 1971.7) 0.485 eBR (%) 30.3 (23.6, 36.9) 28.1 (22.0, 34.3) 37.0 (26.0, 48.1) 0.028 *✝ ✝ * Peak HR (bpm) 147 (141, 153) 128 (122, 134) 119 (108, 129) 0.308 * x x Peak RER 1.13 (1.09, 1.12) 1.09 (1.05, 1.12) 0.97 (0.91, 1.04)* 0.181 Peak RPE 18 (17, 19) 18 (17, 19) 17 (15, 18) 0.072 * x x 1 min HR recovery (bpm) − 36 (− 32, − 40) − 30 (− 26, − 34) − 18 (− 11, −25)* 0.209 + + + 2 min HR recovery (bpm) − 54 (− 50, − 59) − 45 (− 40, − 49) − 32 (− 25, −38) 0.312 + + + 3 min HR recovery (bpm) − 60 (− 56, − 65) − 49 (− 45, − 53) − 37 (− 30, −44) 0.359 + + + 6 min HR recovery (bpm) − 67 (− 62, − 71) − 54 (− 50, − 58) − 41 (− 33, − 48) 0.377 + + + Exercise test duration (s) 963.2 (916.3, 1010.1) 747.8 (703.9, 791.6) 488.3 (409.8, 566.8) 0.635 + + + METs 8.1 (7.8, 8.5) 5.9 (5.6, 6.2) 4.3 (3.7, 4.8) – Maximal CPET (%) 26 (93) 26 (81) 6 (60) 0.058 + ** Achieves 150 min of moderate activity per week (%) 18 (64) 9 (28) 5 (50) 0.011 + ** Achieves 75 min of vigorous activity per week (%) 7 (25) 1 (3) 0 (0) 0.013 VO peak oxygen uptake, VAT ventilatory anaerobic threshold, VE/VCO ventilatory efficiency with respect to CO elimination, VO /HR oxygen pulse, OUES 2peak 2 2 2 oxygen uptake efficiency slope, eBR estimated breathing reserve, HR heart rate, bpm beats per minute, RER respiratory exchange ratio, RPE rating of perceived exertion; S seconds, METs metabolic equivalents **Significant group effect *Significant difference between high CRF and low CRF Significant difference between high CRF and moderate CRF Significant difference between mod CRF and low CRF Significantly different from all other groups Nichols et al. Sports Medicine - Open (2018) 4:22 Page 7 of 11 Table 5 Blood Biomarkers Expressed as Mean (95% Confidence Intervals) Variable High CRF, n = 28 Mod CRF, n = 32 Low CRF, n = 10 Partial eta squared p value ✝ ✝ NT-proBNP (ng/L) 86.1 (11.4, 1428.0) * 217.0 (33.9, 1916.0) 464.0 (26.9, 2735.0)* - < 0.001** Total Chol (mmol/L) 3.6 (3.2, 3.9) 3.7 (3.4, 4.0) 3.9 (3.3, 4.5) 0.017 0.579 LDL Chol (mmol/L) 1.7 (1.4, 1.9) 1.8 (1.6, 2.1) 1.9 (1.4, 2.3) 0.019 0.529 HDL Chol (mmol/L) 1.2 (1.0, 1.3) 1.2 (1.0, 1.3) 1.4 (1.2, 1.6) 0.052 0.176 TC/HDL ratio 3.2 (2.9, 3.5) 3.3 (3.0, 3.6) 3.0 (2.5, 3.6) 0.01 0.713 Triglycerides (mmol/L) 1.6 (1.3, 1.9) 1.5 (1.2, 1.8) 1.4 (0.9, 2.0 0.011 0.691 x x Glucose (mmol/L) 5.7 (3.3, 13.8) 5.2 (4.1, 22.2) 6.4 (5.5, 16.9) - 0.012** hs-CRP (mg/L) 1.4 (0.3, 2.5)* 2.8 (1.7, 3.8) 4.2 (2.3, 6.2)* 0.099 0.033** Neutrophil/lymphocyte ratio 2.4 (2.1, 2.8) 2.8 (2.4, 3.1) 3.3 (2.7, 3.8) 0.084 0.052 + + + Haematocrit (%) 0.423 (0.410, 0.435) 0.405 (0.393, 0.417) 0.376 (.355, 0.397) 0.180 0.001** + + + Haemoglobin (g/L) 145.5 (140.7, 150.2) 138.2 (133.7, 142.6) 125.6 (117.6, 133.6) 0.219 < 0.001** eGFR (mL/min/1.73 m ) 80.2 (75.2, 85.3) 76.2 (71.4, 80.9) 71.0 (62.6, 79.4) 0.053 0.160 NT-proBNP N-terminal prohormone brain natriuretic peptides, Chol cholesterol, LDL low-density lipoproteins, HDL high-density lipoproteins, hs-CRP high-sensitivity C-reactive protein, eGF estimated glomerular filtration rate **Significant group effect *Significant difference between high CRF and low CRF ✝Significant difference between high CRF and moderate CRF Significant difference between moderate CRF and low CRF Significantly different from all other groups annual mortality risk ) despite the risk model not in- the moderate and low CRF groups. This suggests a cluding CRF-based measurements. The CALIBER model greater degree of cardiac dysfunction, ventilatory perfu- includes an extensive set of all-cause mortality predictor sion mismatch, or heightened peripheral chemoreceptor variables, including sociodemographics, CHD severity and sensitivity as seen in patients with CHF [28, 29]. phenotype, primary CVD risk factors, CVD and non-CVD NT-proBNP levels and VE/VCO slopes were higher comorbidities, psychosocial factors, and biomarkers. This even in the absence of significant resting LV impairment. provides further evidence that CRF and other CPET-derived It is possible that patients with CHD and low CRF have variables should be treated as ‘clinical vital sign’ . undiagnosed CHF or are in the early stages of its devel- An important finding of this study was that opment. Future research is required to determine NT-proBNP levels and VE/VCO slopes were highest in whether lower CRF in patients with CHD confers a Fig. 1 Carotid intima-media thickness measurements in low, moderate, and high cardiorespiratory fitness groups. Mean left-sided carotid intima-media thickness measurements (solid grey bars) were higher in the low and moderate cardiorespiratory fitness categories. Mean right-sided carotid intima-media thickness (lines) did not differ between groups. Mod = moderate; CRF = cardiorespiratory fitness *Significant difference between high CRF and low CRF; ✝Significant difference between high CRF and moderate CRF Nichols et al. Sports Medicine - Open (2018) 4:22 Page 8 of 11 Fig. 2 Left- and right-side common carotid artery plaque severity in patients with high, moderate, and low cardiorespiratory fitness. Black bars indicate the proportion of patients with plaques < 1 mm and diagonal lines indicate the proportion of patients with plaques between 1 and 3 mm. Grey bars indicate the proportion of patients with plaques > 3 mm. Mod = moderate; CCA = common carotid artery greater risk of developing CHF. Closer monitoring for CHF, and smoking history do not entirely explain the in- signs and symptoms of CHF may be needed for patients creased mortality risk associated with having low CRF. who enter CR and have low CRF. Physical activity participation and higher CRF have been The prognostic value of a high VE/VCO slope and/or established as important independent causative factors NT-proBNP has been well-described in CHF [30–32]. for recurrent events . In our study, patients defined as However, the value of VE/VCO slope and NT-proBNP having high CRF reported participating in regular phys- levels has also been shown in CHD. Elevated values ical activity and had the lowest 5-year risk of death. This predict all-cause mortality , cardiovascular mortality was accompanied by a lower resting HR and a quicker (~ 5 year follow-up), and the development of CHF and post-exercise HR recovery, indicators of autonomic stroke . A high VE/VCO is independently associated function which also carry prognostic value. Interestingly with high NT-proBNP levels, as well as ventricular re- however, no differences were evident in standard an- modelling . Our findings suggest that patients with thropometric indices (BMI or waist circumference) or in both low and moderate CRF levels are at greatest risk of DXA-derived body fat content across the CRF groups. having such adverse health outcomes, corroborated by The link between cardiometabolic profile, body their higher CALIBER 5-year risk. composition, and cardiovascular risk has been widely Traditional risk factors such as angina symptoms, reported andthere is oftenanemphasisonreducing prior MI, atrial fibrillation, claudication, type II diabetes, overweight and obesity states in CR programmes. In Fig. 3 CALIBER 5-year all-cause mortality risk scores were incrementally higher across the three cardiorespiratory fitness groups. Mod = moderate; CRF = cardiorespiratory fitness+Significantly different from all other groups Nichols et al. Sports Medicine - Open (2018) 4:22 Page 9 of 11 our study, patients with higher CRF had a larger pro- cardiometabolic risk, and increased risk of 5-year all-cause portion of lean tissue and more favourable abdominal mortality. Exercise testing is widely applied in cardiological fat distribution. Low CRF was only associated with la- and CR environments. Longer-term, or higher intensity tent changes in body composition. Changes were not exercise-based CR programmes may help improve the car- evident when assessing patients with routinely applied diometabolic health of patients with CHD and low CRF. anthropometric techniques, such as BMI and waist Abbreviations circumference. Whilst overweight patients with CHD ±: Standard deviation; 95% CI : 95% confidence Intervals; have been reported to benefit from a better prognosis ANCOVA: Analysis of covariance; ANOVA: Analysis of variance; BMI: Body mass index; BP: Blood pressure; CABG: Coronary artery bypass graft; than their leaner counterparts, , the association CCA: Common carotid artery; CHD: Coronary heart disease; CHF: Chronic between higher BMI and reduced all-cause mortality heart failure; C-IMT: Carotid intima-media thickness; CPET: Cardiopulmonary may depend on a patients’ CRF. Those characterised exercise test; CR: Cardiac rehabilitation; CRF: Cardiorespiratory fitness; CV: Cardiovascular; CVD: Cardiovascular disease; DXA: Dual X-ray absorpti- as having low CRF appear to benefit from improved ometry; ECG: Electrocardiogram; EDTA: Ethylenediaminetetraacetic acid; e- survival whilst fitter individuals do not [37, 38]. Our GFR: Estimated glomerular filtration rate; Hb: Haemoglobin; Hct findings (incorporating criterion fitness and ‘fatness’ : Haematocrit; HDL: High-density lipoproteins; HR: Heart rate; hs-CRP: High- sensitivity C-reactive protein; LDL: Low-density lipoproteins; LV: Left measures) suggest that maintaining or improving CRF ventricular; LVEF: Left ventricular ejection fraction; METs: Metabolic may help lower recurrent cardiovascular risk in pa- equivalents; MI: Myocardial infarction; NHS: National Health Service; NT- tients with CHD. However, our sample is relatively proBNP: Terminal pro B type natriuretic peptide; VO /HR: Oxygen pulse; OUES: Oxygen uptake efficiency slope; PCI: Percutaneous coronary small and only 10 patients were identified as having a intervention; RPE: Rating of perceived exertion; SST: Serum separating tube; low CRF (n = 10). This may increase the likelihood of VAT: Ventilatory anaerobic threshold; VE/VCO slope: Ventilatory efficiency statistical error (type I/type II error) when comparing with respect to CO elimination; VO :Oxygen uptake;VO :Peak oxygen 2 2 2peak uptake; η : Partial eta squared CRF groups. However, many of the effect sizes (ηp ) p associated with differences in cardiometabolic risk Acknowledgements were large. Furthermore, the 95% CI indicate distinct We would like to thank Hull and East Riding Cardiac Trust Fund for providing values for many cardiometabolic variables across the financial support enabling blood sample analysis. We would also like to thank Wendy Summer, Lesley Richardson, and Emma Smith for their support CRF groups. However, further research using a larger recruiting patients to this study. patient cohort is required to confirm if our findings are representative of the wider CHD population. Funding As reported by others [4, 6], our data shows that pa- Funding for blood sample analysis was provided by Hull and East Riding Cardiac Trust Fund. tients with high CRF have lower CALIBER 5-year risk scores compared to patients with low and moderate CRF. Availability of Data and Materials In previous studies [4, 6], patients characterised as having The dataset supporting the conclusions of this article are available via request to the corresponding author. high CRF were shown to have superior survival over a 15-year period. Barons and colleagues reported that Authors’ Contributions within their low CRF group, a history of MI, PCI, and an- SN contributed to study design, study management, data collection, data gina were associated with the highest risk of death. Our analysis, and manuscript preparation. CT, RP, AKB, and FN provided extensive support during data collection and manuscript preparation. TG contributed data do not confirm this. However, similar to our findings, significantly to the study design, trial management, and manuscript Taylor et al.  reported that prior MI is not more preva- preparation. ALC contributed to the study design and provided critical lent amongst patients with low CRF. It is possible that size manuscript preparation as well as providing medical support to the study. SC contributed to the study design and data analysis, and reviewed multiple and location of MI are responsible for differences in car- versions of the manuscript. LI contributed significantly to the study design diac dysfunction and mortality risk. and preparation, managed the study, and contributed to the manuscript Patients with a high CRF also had smaller left-sided preparation. All authors read and approved the final manuscript C-IMT measurements compared to patients with moder- Ethical Approval and Consent to Participate ate or low CRF. This may be because patients with a high Ethical approval for the study was given by the Humber Bridge NHS CRF also had a better cardiometabolic profile, including Research Ethics Committee-Yorkshire and the Humber (12/YH/0278). After giving verbal consent, patients were invited for assessment at Academic high levels of self-reported physical activity. Exercise train- Cardiology, Castle Hill Hospital, Kingston-Upon-Hull, where written informed ing can improve cardiovascular risk factor profiles in pa- consent was obtained. tients with CHD  and attenuate C-IMT and carotid plaque progression in as little as 6 to 12 months [40, 41]. Competing Interests Partial salary funding for SN was received by City Health Care Partnership CIC It is however important to acknowledge that older age (Hull, United Kingdom). The authors declare that they have no competing attenuated the relationship between C-IMT and CRF. interests. Conclusions Publisher’sNote Identification of patients with low CRF and CHD appears Springer Nature remains neutral with regard to jurisdictional claims in to be an effective means of identifying those at highest published maps and institutional affiliations. Nichols et al. Sports Medicine - Open (2018) 4:22 Page 10 of 11 Author details 18. Taylor C, Nichols S, Ingle L. A clinician’s guide to cardiopulmonary exercise Centre for Sport and Exercise Science, Sheffield Hallam University, Collegiate testing 1: an introduction. Br J Hosp Med. 2015;76(4):192–5. Hall, Collegiate Crescent, Sheffield S10 2BP, UK. Carnegie School of Sport, 19. Nichols S, Taylor C, Ingle L. A clinician's guide to cardiopulmonary exercise Leeds Beckett University, Fairfax Hall, Headingley Campus, Leeds LS6 3QS, testing 2: test interpretation. Br J Hosp Med. 2015;76(5):281–9. UK. Sport Health and Exercise Science, Don Building, University of Hull, 20. 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