The total cohort completed 36.6 ± 0.5 hours of EECP treatment. EECP treatment improved the CCS class in 79% of the patients with chronically stable angina pectoris (Figure 1). The mean value of CCS classes prior to EECP treatment were significantly higher as compared to mean value after EECP treatment (3.0 ± 0.1 as compared to 2.2 ± 0.1, p < 0.001). The angina functional class did not change in 21% of the patients and importantly no patient changed to a higher CCS class directly after EECP treatment. Most angina patients (89%) were in CCS class III and IV pre-EECP treatment and 79% of these patients reduced their angina with at least one CCS class. The improvement in CCS class was significant in patients with CCS class III and IV and persisted six and 12 months after EECP treatment, while there was no such reduction in angina status in patients with CCS class II (Figure 2). Most patients improved one CCS class (73 ± 7%), thus 27 ± 7% of the patients improved two CCS classes and the beneficial effects were sustained at the 12-months follow-up. The improvement of two CCS classes tended to be more prominent in patients with CCS class IV prior to the EECP treatment and progressed over a six month period. 86% of the patients in CCS class IV prior to the EECP treatment improved in angina functional class. All of the patients that had improved two CCS classes had done this within six months after the treatment. During the follow-up period one patient died six month after EECP treatment in a myocardial infarction.

The weekly nitroglycerin usage was decreased after EECP treatment. 87 ± 5% of the patients used nitroglycerin before EECP treatment and 63 ± 7% used nitroglycerin after EECP treatment (p < 0.01). The other daily medication remained unaltered.

All patients underwent the initial phase of the EECP treatment without problems. However, during the EECP treatment period, adverse events were noted in eight cases which forced them to terminate their treatment (Table 3). They were not included in the follow-up investigations. One patient died after 15 treatment sessions. The death was considered as sudden death with no sign of worsening of the angina immediately before the death. One patient suffered from a myocardial infarction between treatment sessions nine and ten. The patient died in a myocardial infarction two weeks after termination of the EECP therapy. Two patients had increased chest pain and four patients had gastrointestinal problems.

Discussion

The present study is the first long-term systematic follow-up study from a Scandinavian centre of consecutive patients treated with EECP for chronic stable refractory angina pectoris. The majority of the patients were men and showed a profile of extensive coronary artery disease, previous revascularizations and a poor quality of life. The patients were not available for further coronary revascularization and were on optimal pharmacological treatment. The medical regimen was not changed during the EECP treatment.

The results from the present study confirm that EECP treatment significantly reduces the CCS class in patients with chronic stable angina pectoris, which is in accordance with previous American studies [8,15-17]. It was noted that there was a significant decrease in the frequency of anginal episodes and nitroglycerin usage. EECP increases diastolic aortic pressure, reduces systolic pressure and enhances venous return, thus resulting in increased cardiac output [18]. However, the mechanisms by which these hemodynamic effects lead to a reduction of angina are poorly understood, although the effect is similar to IABP [11]. There is accumulating evidence suggesting that EECP treatment improves endothelial function, which may contribute to the clinical benefit [12]. EECP treatment is associated with an immediate increase in blood flow in multiple vascular beds including the coronary arterial circulation [11]. This increase in blood flow may result in increased endothelial shear stress [19], which enhances endothelial function by stimulating the release of the vasodilatory mediator nitric oxide and reduces the release of the vasocontractile endothelin-1 [18,20-22]. Furthermore, besides the release of metabolites from ischemic regions, an increase in endothelial shear stress is considered a major stimulus for collateral blood vessel development and recruitment [23]. This suggests that EECP treatment may exert its clinical beneficial effect by enhancement of coronary collateralization. EECP therapy has been associated with the release of angiogenic factors, such as vascular endothelial growth factor [23], basic fibroblast growth factor and hepatocyte growth factor [24].

The relief in CCS class was seen in patients with CCS class III and IV, while there was no beneficial effect in patients with CCS class II. Previous studies have shown a beneficial effect even in patients with mild angina [25]. The reason for the lack of effect in patient with CCS class II in the present study may be due to the limited number of patients in this group. These results indicate that the EECP treatment may be more effective in patients with the most disabling angina, which is in accordance with previous findings [26]. The reason for this is not known, although given the important role of shear stress for endothelial function, the shear stress forces may be stronger in patients with severe angina as compared to patients with mild angina [20,21]. Also, it might be easier for a patient to experience an improvement from CCS class IV to III, as compared to CCS class II to I, due the classification scale of the different angina functional classes.

73% of the patients who experience a beneficial effect of the EECP treatment improved one CCS class, and 27% of the patients improved two CCS classes. The relief of two CCS classes tended to progress over a period of six months and was more prominent in patients with CCS class IV prior to the EECP treatment. This delayed improvement in functional angina class has, to our knowledge, never been reported before. It is furthermore noteworthy that the improvement persisted in the 12-months follow-up. In a previous study by Masuda and colleagues it was shown that the plasma levels of nitric oxide is not increased immediately after completion of therapy but one month after [22]. One possible explanation to this delay may be an up-regulation of the endothelial nitric oxide synthase, the major source of endothelial nitric oxide [22]. This would result in a delay of improved endothelial function [27], and may explain the sustained effect of EECP treatment seen in the present study. Furthermore, the indication of EECP treatment promoting angiogenesis could also be an explanation to the delayed and persistent beneficial effect of the current treatment [28].

When stopping medical treatment or physical training no beneficial effect would be expected in a 12 months follow-up. Although, long-term effects after EECP treatment have been confirmed in the present study and in previous clinical [9,13,29] and observational studies [14,18]. The pathophysiological explanation for the long-term effects is not fully understood and need further studies. Thus, the initial improvement in CCS class after EECP therapy allows more physical activity [29], which may induce similar stimuli as EECP treatment [12].

Limitation of the study

The present study is a follow-up report that does not include a control group, therefore a possible placebo effect can not be excluded. The improvement in CCS class could in such a case be a result of special attention of the patients during the follow-up and also statistically regression towards mean. The adverse events are in accordance with what is normally seen in this type of patients and there was no increase due to the EECP treatment. Thus, EECP therapy appears to be a promising alternative treatment to patients with severe refractory angina pectoris where medical treatment and surgical procedures are exhausted.

Conclusion

The present study is the first to evaluate the effect of EECP treatment at a Scandinavian centre on patients with refractory angina pectoris. In summary, we found that EECP is a safe treatment for highly symptomatic patients with refractory angina. The effects were sustained in most of the patients at a 12-months follow-up. These results verify that the EECP treatment should be considered as an alternative treatment for patients with chronic refractory angina.

Competing Interest

The author(s) declare that they have no competing interests.

Author's Contributions

TP was responsible for the treatment of the patients and was involved in initiating and designing the study and drafted the manuscript along with OO. SB and DD treated the patients and collected the data. AW was involved in analyzing the data and writing the manuscript. LE supervised the collection of data and writing of the final manuscript. All authors have read and approved the final manuscript

Acknowledgement

This study has been supported by the Swedish Medical Research Council Grant 5958, and the Swedish Heart Lung Foundation.