Exercise training is accepted as a fundamental non-pharmacological intervention strategy in cardiac rehabilitation (Normandin et al., 2013). For training therapy, extensive research looking at the individual dose-effect relationship should be standard practice as it is for pharmacological interventions (Church and Blair, 2009). The participation of vigorous-intensity aerobic exercise (Haskell et al., 2007) as well as high- to severe-intensity aerobic interval exercise (Mezzani et al., 2012) is encouraged by current guidelines and recommendations. The various beneficial effects yielded by aerobic high-intensity interval training in heart disease patients are well documented (Juneau et al., 2014; Warburton et al., 2005). In particular, maximal oxygen uptake ([VO.sub.2max]), which has been noted as the best single predictor of death among cardiac patients (Kavanagh et al., 2002), was found to be improved through high-intensity interval exercise (HIIE). These improvements were observed to be similar (Conraads et al., 2015) or even greater compared to moderate continuous exercise training (Arena et al., 2013; Haykowsky et al., 2013; Wisloff et al., 2007). Therefore, aerobic high-intensity interval training has been reported to be an effective alternate to conventional continuous endurance training in cardiac rehabilitation (Gibala et al., 2012; Guiraud et al., 2012).
However, since the peak workload in aerobic HIIE is usually higher than in moderate continuous exercise (moderate CE), the acute physiological responses and, consequently, the potential risk of adverse events, may be increased during HIIE (Arena et al., 2013; Rognmo et al., 2012; Keteyian, 2012; Thompson et al., 2007). Though Rognmo et al. (2012) found low event rates during both moderate CE (1 event per 129456 exercise hours) and HIIE (1 event per 23182 exercise hours), Keteyian (2012) argued that an exploratory interpretation of these data might be that moderate CE is safer than HIIE. As emphasized by Arena et al. (2013) and our own working group (Tschakert and Hofmann, 2013), both the adverse event risk and the achieved beneficial effects may vary between different HIIE protocols (Mezzani et al., 2012). More precisely, health risks and training adaptations are caused by the acute physiological responses yielded by particular interval protocols depending on the setting of the single HIIE determinants (intensity and duration of the peak workload and recovery phases and the resulting mean load, respectively). Therefore, it is highly relevant to discover which HIIE prescription is most suitable for cardiac patients with respect to both safety and efficiency (Arena et al., 2013; Gibala et al., 2012).
With respect to the particular setting of HIIE, the fundamental findings of Astrand et al. (1960) and Saltin et al. (1976) revealed that a great amount of work at high intensities can be obtained with clear submaximal circulatory and respiratory load by an appropriate application of short work periods. These findings were supported by recent investigations in healthy individuals (Tschakert et al., 2015) and patients with type 1 diabetes mellitus (Moser et al., 2015).
The number of studies investigating the acute response to aerobic HIIE in cardiac patients, however, is rather small. The impact of different HIIE protocols on the acute physiological response was investigated in chronic heart failure (CHF) patients (Meyer et al., 1996; 2012) and in subjects with stable coronary heart disease (CHD) (Guiraud et al., 2010). Meyer et al. (1996) did not find essential differences in the acute metabolic, cardiac, and hormonal response between the HIIE modes, whereas Guiraud et al. (2010) and Meyer et al. (2012) found short HIIE to be more effective with respect to the time to exhaustion, the time spent near [VO.~sub.2max], and rating of perceived exertion (RPE) compared to long intervals. Cardiac risk markers such as cardiac troponin T (cTnT) and creatine phosphokinase MB (CK MB) which are biomarkers of cardiac injury, and B-type natriuretic peptide (NT-proBNP), a marker for cardiomyocyte stress (heart failure), as well as Lipoprotein-associated phospholipase [A.sub.2] ([Lp-PLA.sub.2]), a platelet-activating factor, were not measured.
Few studies have investigated the acute physiological response yielded by certain HIIE protocols compared to CE in cardiac patients. No significantly different response for cardiac biomarkers (Benda et al., 2015; Normandin et al., 2013), endothelial microparticles (Guiraud et al., 2012; 2013), hemodynamic markers and arteriovenous [O.sub.2]-difference (Gayda et al., 2012; Meyer et al., 1998), respiratory markers (Normandin et al., 2013), Creactive protein (Normandin et al., 2013), and RPE (Normandin et al., 2013) were observed between HIIE and CE, despite markedly higher peak intensities in HIIE. In these studies, HIIE and CE were isocaloric (Benda et al., 2015; Guiraud et al., 2012; 2013; Normandin et al., 2013) or matched for mean load (Meyer et al., 1998). However, no HIIE protocols with peak workload durations longer than 1 min were applied in these investigations. Meyer et al. (2012) used longer peak workload durations of 90 s for intermittent exercise but did not compare HIIE vs. CE.
The question arises which HIIE protocol is most convenient for cardiac patients. Guiraud et al. (2010) and Meyer et al. (2012) suggested HIIE protocols with short tpeak and passive recovery to be more convenient than HIIE with long [t.sub.peak] and active recovery. Benda et al. (2015) and Guiraud et al. (2011, 2012) suggested highly intense exercise stimuli to the peripheral muscles without great cardiovascular stress to be possible by using intermittent exercise with short bouts of work followed by short recovery periods. In line with that, Meyer et al. (2012) and Conraads et al. (2015) suggested long intervals, such as the 4 x 4 min model, to be problematic since patients can hardly sustain 4 min intervals at high intensities. In contrast, Arena et al. (2013) favors HIIE with long [t.sub.peak] similar to the "Norwegian" model which is frequently applied in scientific studies and practice in patients suffering from different chronic diseases (Helgerud et al., 2010; Rognmo et al., 2004; Tjonna et al., 2008; Wisloff et al., 2007). However, as emphasized by Normandin et al. (2013), the acute physiological responses to the 4 x 4 interval mode, or to similar HIIE protocols applying a longer tpeak (Warburton et al., 2005), were not published.
Therefore, the aim of our study was to investigate the acute response for metabolic, cardiorespiratory, and plasma parameters such as cardiovascular and inflammatory markers and catecholamines, in patients undergoing phase III cardiac rehabilitation. The test protocols which were applied in the study included short (20 s) and long (4 min) HIIE and moderate CE matched for mean load and total duration.
We hypothesized that during short HIIE, mean and peak values for lactate (La) as well as peak values for heart rate (HR) and oxygen uptake ([VO.sub.2]) will be similar to CE but significantly lower compared to long HIIE despite a markedly higher [P.sub.peak] in short HIIE. However, we hypothesized that the exercise-induced changes in the concentration of cardiovascular biomarkers, catecholamines, and inflammatory markers will not significantly differ between CE, short HIIE, and long HIIE, indicating that all three exercise tests can be performed safely.
Eight patients undergoing phase III cardiac rehabilitation (7 males, 1 female; age: 63.0 [+ or -] 9.4 years; height: 1.74 [+ or -] 0.05 m; weight: 83.6 [+ or -] 8.7 kg; [VO.~sub.2max]: 21.6 [+ or -] 7.6 ml x [kg.sup.-1] x [min.sup.-1]) participated in this study. Preceding coronary incidences ( 8 weeks) included coronary heart disease (CHD; n = 7) and myocarditis without CHD (n = 1). Left ventricular ejection fraction (LVEF) was [greater than or equal to] 45 % in all subjects. Seven of eight patients were treated with [beta]-blocking agents during the study (Table 1). The experimental protocol was approved by the ethics commission of the Medical University of Graz, Austria (EK decision number 23-397 ex 10/11). The test design, and potentially associated health risks, were explained to all subjects who gave their written informed consent before participating in the study. They were familiar with the cycle ergometer exercise in the cardiac rehabilitation center (ZARG, Graz, Austria) where all tests were performed within the rehabilitation program under medical supervision.
At the beginning of the study, the subjects performed a maximal symptom-limited incremental exercise test (IET) in order to assess the maximum aerobic power output ([P.sub.max]), [VO.~sub.2max], and maximum heart rate ([HR.sub.max]), as well as the first and second lactate turn point ([LTP.sub.1], [LTP.sub.2]) referring to the three phase model of metabolism (Hofmann and Tschakert, 2011) and to the Lactate Shuttle Theory by Brooks (Brooks, 2009). [LTP.sub.1] and [LTP.sub.2] were accordant with the first ([VT.sub.1]) and second ventilatory threshold ([VT.sub.2]) and were used for exercise intensity prescription for HIIE and CE.
Then, the participants performed three specific exercise tests: short HIIE (A), long HIIE (B), and CE (C). Importantly, all exercise tests were matched for mean load ([P.sub.mean]) and total exercise duration. The testing sessions were randomly assigned and interspersed by at least 2 days.
Incremental Exercise Test (IET)
The IET started with a resting period of 1 min (0 W) and a subsequent warm-up phase at 10 Watt (W) also for 1 min. Then, the power output was increased by 10 W per minute until (symptom-limited) exhaustion according to the standard protocol of the Austrian Society of Cardiology (Wonisch et al., 2008). A 3 min cool-down period at 10 W finalized the IET.
[LTP.sub.1] and [LTP.sub.2] were determined by means of computer-aided linear...