The present study is the first retrospective study evaluating early CR in patients with heart failure after AMI following PCI. The main findings of this study suggest that early CR was able to reduce cardiogenic death in patients with HFrEF, and reduce re-hospitalization in patients with HFmrEF after AMI. Furthermore, the intervention was safe; PETCO2 at VT was an independent risk factor for re-hospitalization.
In patients with HF, research suggested that exercise-based CR could improve QoL, decrease all-cause hospital admissions and HF- dependent hospital admissions in the short term (up to 12 months) and potentially reduce mortality in the long term when compared to no exercise patients [16, 17]. Our study expands the previous research by showing that early rehabilitation program involving supervised regular exercise and electrical stimulation can reduce the incidence of cardiac death in patients with HFrEF, and heart failure re-hospitalization in patients with HFmrEF. Elevated serum potassium level and CR ratio were independent risk factors for cardiac death in HFrEF patients after AMI. Moreover, our study suggests that sex, age,history of stroke, and elevated serum potassium were independent risk factors for re-hospitalization in patients with HFmrEF after AMI. Thomsen et.al also reported that hyperkalemia was strongly associated with the degree of renal dysfunction and severe clinical outcomes as well as death in HF patients [18]. Houchen et.al found that a 6-week early rehabilitation program including exercise and self-management education, improved short-term exercise tolerance and depression [7]. However, the sample size was small in this study and there was no control group for comparison. With a larger study population and a non-CR control group, out results suggest that early CR was not only effective but also safe in patients with CHF soon after AMI.
Exercise intolerance is a major feature of CHF, and is associated with impaired QoL, reduced functional capacity and poor prognosis. In addition to reduced cardiac function, other causes such as reduced pulmonary reserve, impaired skeletal muscle function, etc can diversely and significantly contribute to the syndrome in CHF patients, and even turn into the dominant mechanisms of exercise intolerance [19]. Exercise can provide numerous benefits for CHF patients including decreased long-term morbidity and mortality [20], improved cardiac remodeling [21], increased neurovascular functional competency [22], reduced re-hospitalization and improved of cardiorespiratory capacity and QoL [1, 23]. The benefits of electrical stimulation included improving blood supply and muscle strength, as well as exercise tolerance in severe CHF patients [24, 25], so it could be offered as an alternative to bicycle training as part of a home-based rehabilitation program [10]. In our study, the re-hospitalization in patients who accepted the 2-week CR after PCI was only related to CRF, but not to serum potassium level or history of diabetes. The reason may be related to the protective effects of exercise on renal function and the improvement of glycolipid metabolism. Our previous research suggested that upregulation of nitric oxide synthases in the kidney and left ventricle may contribute, in part, to the renal and cardiac protective effects of exercise training in cardio renal syndrome in chronic heart failure rats [26]. Furthermore, exercise can reduce early diabetic nephropathy by upregulating nitric oxide synthases as well as ameliorating NADPH oxidase and α-oxoaldehydes in the kidneys of ZDF rats [27].
CRF is now being considered as an essential variable and should be assessed in health screenings [28]. The clinical values of CRF assessment include diagnosis, functional evaluation and prognosis prediction. CPX is the most precise tool to determine exercise tolerance and considered as the reference clinical procedure for assessing CRF by quantifying peak VO2 which represents an individuals' capacity to generate energy for strenuous exercise [28]. CHF is a systemic syndrome with the reduction of functional reserve being the outstanding characteristic. The cardiovascular impairment has a direct negative effect on other systems and organs, including the respiratory, renal and neuromuscular systems. CPX is defined as “gold standard” for the CRF of patients with cardiovascular disease, the clinical diagnosis assessment and prognosis prediction can be achieved from direct measurement of VO2, VCO2 and VE [29]. The characteristic of CPX data in patients with CHF are: decreased VO2 at VT < 40% of the predicted VO2max, O2 pulse < 85% and as a plateau, increased VE/VCO2, wide breathing reserve and usually normal O2 saturation [29, 30]. Weber et al. first published a classification for peak VO2 results: class A, VO2 > 20 ml/kg/min; class B, VO216-20 ml/kg/min; class C, VO210-15 ml/kg/min; and class D, VO2 < 10 ml/kg/min [31]. Arena et al. further proposed the classification based on ventilation/carbon dioxide production relationship (VE/VCO2 slope) values: class I, VE/VCO2 slope ≦ 29.9; class II, VE/VCO2 slope 30-35.9; class III, VE/VCO2 slope 36-44.9; class IV, VE/VCO2 slope ≧ 45 [32]. Ferreira et al. noted that the cutoff point of VE/CO2 slope ≧ 43 would be an appropriate hallmark for heart transplantation determination [33]. Chua et al. found that CHF patients with VE/VCO2 slope > 34 were at very high risk for death and re-hospitalization [34]. The 2012 EACPR/AHA scientific statement endorsed that peak VO2 and VE/VCO2 slope are the most studied CRF variables in CHF patients and both indicated significantly independent prognostic value [11]. For patients under medical treatment, a peak VO2 < 10.0 ml/kg/min and a VE/VCO2 slope ≧ 45 exist at the same time would indicate a very poor prognosis over the following 4-year [11]. It should be noted that, in order to achieve the prediction accuracy of peak VO2 value on CHF, maximal exercise (at least RER > 1.05) should be achieved during the test [29]. Others evaluating the long term prognosis by VE/VCO2 slope in CHF, and reported that it was an excellent independent value, even better than peak VO2, and could be achieved only from sub-maximal exercise [35, 36]. Similarly our results indicated that CR patients with VE/VCO2 slope < 36 had a good cardiovascular prognosis.
However, it is difficult to achieve a maximal test in most CHF patients due to the exercise intolerance. The 2016 EACPR/AHA updated the scientific statement, and felt that it is important to note that VO2 at VT holds broad applicability in the context of assessing the capacity [37]. The VO2 at VT has also been indicated as a hallmark for the prognosis prediction prior to surgery [38, 39]. Furthermore, we also showed that VO2 at VT is a significant prognostic marker for AMI patients in whom a VO2 at VT < 10.5 ml/kg/min indicated a poor long term prognosis [40]. The PETCO2 both at rest and in exercise have been found to be positively correlated with the prognosis of systolic heart failure [41]. Abnormalities in the VE/VCO2 slope and PETCO2 in patients with HCM have been thought to enhance pulmonary pressures [31, 41]. In the present study, we noted that PETCO2 at VT was also a predictor of re-hospitalization for patients with CHF after AMI, previous study showed that a lower PETCO2 was associated with a poor prognosis [40].
Our previous study demonstrated that VO2 at VT was an independent risk factor for cardiovascular disease prognosis and could be used as an evaluating hallmark for Phase I cardiac rehabilitation in patients with STEMI after PCI[40]. However, the PETCO2 at VT is an independent risk factor for re-hospitalization in patients with heart failure after AMI. The reasons of the difference may be as follows: first, patients with STEMI after PCI may not have reduced ejection fraction and severe pulmonary dysfunction after PCI operation, a smaller amount of PETCO2 is an indicator of less CO2 production in the body and/or pulmonary arterial perfusion, or in other words, the cardiac output [42]. The difference in PETCO2 might be attribute to the difference in infarct location. VO2 at VT is determined not only by the degree of the infarct area but also the peripheral oxygen utilization efficiency, and could be an independent risk factor for the prognosis in patients with STEMI after PCI. Second, ventilation is regulated by the sensitivity of respiratory chemo-receptors and the ergo reflex in skeletal muscles. The sensitivity of respiratory chemo-receptors increases when the sympathetic nerve is activated and/oracidosis occurs. These conditions often occur in HF patients [43]. These subjects experience shortness of breath throughout mild to vigorous activity. While in insufficiently expansion and with increased dead space between artery and alveolus, diffusion of CO2 is less, hence, PETCO2 decreases. The re-hospitalization associated with exercise intolerance in patients with CHF are multifactorial, including impaired cardiac and pulmonary reserve, and decreased respiratory and peripheral skeletal muscle function, all of them can diversely and significantly contribute to the decrease in PETCO2. The combined aerobic/resistance/inspiratory training in patients with CHF has been shown to produce positive changes in left ventricular structure and function, which provided additional benefits in both peripheral and diaphragmatic muscle function, dyspnea, cardiopulmonary exercise parameters and QoL [44].
The limitations of this study include: 1) this is a retrospective study in which patients were not randomly assigned to CR or non-CR group, thus selective bias cannot be avoided; 2) patients in the non-CR group were not assessed for CRF using CPX before discharge; 3) the number of MACE in the early CR group was relatively small. Therefore, further research is needed to confirm the influence of CPF parameters on prognosis prediction and the accuracy of cut-off point value.