Physical exercise and quantitative lower limb collateral function

Study design and patients

This was a prospective observational study in 110 patients undergoing coronary angiography for diagnostic purposes in the context of chest pain. The primary study end point was pressure-derived collateral flow index (CFI; see below for calculation) as obtained during a 3 min left SFA balloon occlusion (figure 1). The secondary study end point was the simultaneously measured transcutaneous left calf partial oxygen pressure (PO₂ in mm Hg) divided by transcutaneous PO₂ at a non-ischaemic reference site (figure 2). As independent variables, the items of the Global Physical Activity Questionnaire (GPAQ11) and physical exercise performance as obtained during a bicycle or treadmill exercise test were determined. Criteria for study inclusion were age >18 years, written informed consent to participate in the study, 0-vessel to 3-vessel chronic stable coronary artery disease (CAD), and a complete data set with regard to the primary study end point, to the completed GPAQ and maximal workload in the physical exercise test. Exclusion criteria were acute coronary syndrome, previous myocardial infarction in the vascular region undergoing coronary CFI measurement, severe hepatic or renal failure (creatinine clearance <15 mL/min/1.73 m²). The study was approved by the ethics committee of the Kanton of Bern, Switzerland, and all patients gave written informed consent to participate.

Cardiac catheterisation and coronary angiography

Patients underwent left heart catheterisation and coronary angiography for diagnostic purposes from the right femoral artery approach via a 65 cm-long 8F introducer sheath. Biplane left ventriculography was performed followed by coronary angiography. Coronary artery stenoses were assessed quantitatively as per cent diameter reduction using the guiding catheter for calibration. Aortic pressure (P_ao) was obtained via a 6F or 8F arterial guiding catheter. Central venous pressure (CVP) was measured as right atrial pressure via the right femoral vein. CFI was also determined in one of the coronary arteries, whereby it was measured and calculated as subsequently described for the left SFA.

Invasive collateral assessment

Invasive study protocol

Immediately before the invasive exam, transcutaneous PO₂ sensors were applied after skin preparation. Skin areas with large veins, skin defects or scars were avoided for sensor placement. The controlled heating element around the sensor was adjusted to 44°C, and sensor readings were allowed to stabilise for at least 20 min before the relevant measures were taken. The PO₂ sensors were placed at the left anteromedial calf, halfway below the knee (ischaemic site), and at the lower left abdomen (non-ischaemic reference site). Also, before the diagnostic examination, two puffs of oral isosorbidedinitrate were given. Following diagnostic coronary angiography, and at the start of the invasive study procedure, all patients received 10 000 units of heparin intravenously. The coronary artery undergoing CFI measurements was chosen on the basis of ease of access in case of a non-stenotic vessel, or the presence of a stenotic lesion requiring percutaneous coronary intervention. Coronary fractional flow reserve (FFR) was obtained prior to coronary CFI. FFR was determined with the pressure guide wire positioned distally in the non-occluded coronary artery of interest using an intracoronary bolus of approximately 70 μg adenosine for hyperaemia induction: FFR=distal coronary pressure divided by P_ao. For coronary CFI measurement, an adequately sized monorail angioplasty balloon catheter (diameter ranging 2.5–5 mm) was positioned in the proximal part of the vessel, while the pressure guide wire remained distally. During vessel occlusion, simultaneous coronary P_occl, P_ao and CVP were obtained for the calculation of CFI. Right atrial pressure was taken as CVP via a 5F pigtail catheter. Following coronary CFI measurement, left SFA CFI measurement was performed by crossover technique via the right femoral artery 8F introducer sheath using an over-the-wire 10–12 mm angioplasty balloon (3 min occlusion). CVP was taken at the right atrium. Simultaneously, transcutaneous PO₂ measurements were recorded. The arterial balloon occlusion occurred at an inflation pressure of 1–2 atmospheres. Complete arterial occlusion was established by angiography. Immediately following the CFI measurements, vessel integrity was tested by angiography.

Physical exercise test

Data from a recent treadmill or bicycle exercise ECG test, as performed for diagnostic purposes in the context of chest pain, was obtained from the hospital charts. The independent (and universally available) variable employed for this study was maximal physical workload in watts.

Global Physical Activity Questionnaire

Using the structured GPAQ, information was gained on the time spent performing different types of physical activity in a typical week.15 The questionnaire consists of 16 questions covering the intensity level and estimated time spent during work and leisure time physical activity, as well as during travel to and from places using physical work. According to the patient's mother tongue, the German or French language version of the questionnaire was mailed to the patients following the invasive SFA CFI assessment. The GPAQ has been extensively validated.16 ,17

Statistical analysis

For the purpose of data presentation, two study groups, that is, with absence or presence of intensive leisure time physical activity were formed based on the information gained from the GPAQ. Between-group comparison of continuous demographic, clinical, angiographic, haemodynamic variables and CFI data was performed by an unpaired Student t test. A χ² test was used for comparison of categorical variables among the study groups. Linear regression analysis was performed for testing associations between independent variables (transcutaneous PO₂ index and maximal workload achieved during exercise test) and the dependent primary study end point (left SFA CFI). Linear regression, and Bland-Altman bias and limit of agreement (LOA: bias ± 1.96 SDs) were used to estimate the agreement between the different collateral function modalities. Statistical significance was defined at a p-level <0.05. Continuous variables are given as mean and SD.

Patient characteristics and clinical data

There were no statistically significant differences between the groups regarding age, rate of male gender, weight, height, body mass index, occurrence of cardiovascular risk factors and intake of cardiovascular drugs (table 1).

Haemodynamic and physical exercise data

Mean systemic arterial blood pressure, heart rate, left ventricular ejection fraction, and left ventricular end-diastolic pressure were similar between the groups (table 2). The duration between the invasive exam with SFA CFI measurement and the physical exercise test was not statistically different between the groups. Patients who did not report engaging in intensive leisure time physical activity achieved a lower maximal workload during the exercise test than did patients of the group with intensive leisure time physical activity (table 2). By definition, patients of the group without intensive leisure time physical activity evaluated the respective duration to be 0 min/week (table 2). There was a trend towards shorter estimated durations of intensive physical work and travel, by exercise in the group without versus with engagement in intensive leisure time activity (table 2); the other GPAQ items did not differ among the groups.

Coronary stenosis and collateral function data

Coronary stenosis of the vessel undergoing CFI measurement was more severe both structurally and functionally in the group without versus with reported engagement in intensive leisure time physical activity (table 2). Conversely, coronary CFI revealed a trend towards lower values in the group without versus with engagement in intensive leisure time physical activity. Left SFA CFI tended to be lower in the group without versus with engagement in intensive leisure time physical activity (table 2 and figure 3). The left SFA of all patients was free of stenotic lesions.

Left SFA transcutaneous PO₂ index as obtained in 86 patients, was directly and closely associated with simultaneous left SFA CFI (figure 4). Bland-Altman bias between the two methods was +0.065, and the limits of agreement −0.18 and +0.31. Maximal workload achieved during a previous physical exercise test correlated directly with left SFA CFI (figure 5). All the other continuous parameters as obtained by the GPAQ (estimates of the different work, leisure time and physical travel items in minutes per week; see also table 2) were not associated with SFA CFI.

Exercise and collateral function: clinical evidence

There are currently four treatment modalities reportedly reducing disability and walking distance in intermittent claudication, the most common symptom of lower limb PAD: physical exercise training, cilostazol, percutaneous intervention of pad, and surgical bypass.18 According to expert consensus,19 supervised exercise training is the primary treatment modality for patients with intermittent claudication.7 ,20 ,21 Furthermore, the efficacy of even non-supervised physical exercise training appears to be agreed upon.8 However, given the frequently employed non-specific clinical end point of walking distance, the mechanism (ischaemic preconditioning, training-induced muscle conditioning, collateral promotion) by which exercise exerts its positive effect remains elusive. In cross-sectional, as opposed to longitudinal PAD studies, the association of exercise training/performance and lower limb collateral circulation has, however, been directly addressed by using walking distance as an end point for exercise performance and not, implicitly, for the collateral circulation, which ought to be determined on its own. For example, using MRI of the SFA and collateral vessel number, McDermott et al10 found that the 6 min walking distance lost by SFA occlusion (from 1169 with patent SFA to 1031 feet) was overcompensated for by the presence of ≥8 collaterals (1246 vs 1064 feet with 0–3 collaterals). The selection of patients with total SFA occlusion in that study elegantly circumvented the pitfall of a variable influence of different SFA stenoses on collaterals. In analogy, the present study employed an artificial instead of natural SFA occlusion in the absence of SFA stenotic lesions, thus, also correcting for the diverse arteriogenic influence of varying severities of stenosis. Variable severities of stenosis instead of fixed ones (no stenosis or complete occlusion), could actually lead to opposite findings as in the just cited recent study,10 that is, a higher collateral degree associated with a reduced prevalence of asymptomatic PAD.22 In other words, the collateral circulation is both a benefactor against, and a marker for, the severity of atherosclerosis, the methodological conundrum of which has been resolved in the present study by directly measuring the SFA collateral function, and by determining two potential independent predictors, that is, GPAQ items and maximal workload achieved in an exercise test.

Most commonly used questionnaires to assess functional status and general as well as disease-specific quality of life in patients with intermittent claudication do not include GPAQ.23 To the best of our knowledge, physical activity questionnaires have not been used so far in the context of lower limb collateral function. In patients with CAD, the level of leisure time physical activity, as scored by a structured but not validated questionnaire, and coronary CFI, have been documented to be directly associated.24 In the present investigation, this result could be essentially confirmed, though the current as opposed to the past study population had much less severe stenosis in the coronary artery undergoing CFI measurement. Interestingly, coronary stenosis severity in the CFI vessel tended to be more pronounced among patients without versus with reported leisure time physical activity (see table 2); and nevertheless, coronary CFI was higher among patients engaging in leisure time physical activity. Though the coronary circulation was not in the focus of this investigation, the respective results anchor its main findings. GPAQ has been extensively validated,16 and its German version has also been employed in a recent survey on self-reported physical activity across Germany as obtained by a telephone interview.17 By comparison, the present study gained GPAQ data by telephone interview only in a minority of approximately 10% of the entire study group, that is, in those patients who did not answer the first call to fill out the questionnaire. Answering the GPAQ unassisted certainly complicated the questionnaire's part in which total physical activity durations in minutes per week had to be estimated. This is reflected by the study result that only a dichotomous GPAQ item, the grouping variable, ‘intensive leisure time physical activity’, was mirrored by maximum physical workload.

Maximal workload and quantitative SFA CFI

Maximum physical workload achieved as a continuous parameter is not dependent on an educated guess, and as such, is likely more dependable than certain GPAQ items. This appears the most probable explanation for a mere trend towards a relation between (some) GPAQ items and SFA CFI versus an actual significant and direct correlation between maximum workload and SFA CFI. However, figure 5 illustrates that approximately 92% of the SFA CFI variability was explained by parameters other than varying maximum workload. The key factor contributing to the ‘noise’ in the relation between maximum workload and SFA CFI is the time lag between the exercise test and SFA collateral function measurement. On average, the exercise test had been performed 90 days before the invasive exam with SFA CFI, and the time interval between the two events ranged from 5 years before to 1.5 years after the invasive exam. As a theoretical alternative for the scatter between the two variables, SFA CFI did not accurately reflect quantitative SFA collateral function.

Validation of quantitative SFA CFI

This hypothesis was tested in 80% of the study patients by simultaneous comparison of SFA CFI with an independent, quantitative method, transcutaneous PO₂ index. It was falsified by documenting a tight and direct association between the two independent methods. Bland-Altman bias between the two methods was +0.065, and the limits of agreement −0.18 and +0.31. The trend to underestimate CFI with higher collateral function values might serve as an explanation for the flat rather than more steep relation between maximum workload and SFA CFI. Conversely, the PO₂ method, though employed and validated in the past,25–27 may have technical shortcomings challenging its reference status. Notwithstanding, there was also (at least trend-wise; p=0.12) a direct association between maximum workload and transcutaneous PO₂ index.

Study limitations

The study limitations alluded to and discussed above were the method of GPAQ data acquisition by unassisted written inquiry, and the time lag between obtaining physical exercise data (GPAQ or exercise test) and SFA CFI measurement. Both limiting factors may have influenced the results against the study hypothesis, thus conserving the null hypothesis of no relation between these potential predictors and SFA collateral function.