Wednesday, 1 January 2014

Enhanced external counterpulsation: mechanisms of action and clinical applications


Vasiliki KITSOU1, MD; Theodoros XANTHOS1, PhD; Robin ROBERTS2, George M. KARLIS1, MD; Lila PADADIMITRIOU1, PhD
1Department of Experimental Surgery and Surgical Research, University of Athens, Greece; Medical
School; 2Consultant Cardiologist London, UK.
---------------------------------------------------------------------------------------------------------------------------------

Symptomatic coronary artery disease (CAD) and heart failure (HF), either of ischaemic or nonischaemic aetiology, are common medical problems. Despite optimal medical treatment and improved revascularisation techniques, a significant number of patients are not successfully managed. Among the non-pharmacological, alternative, non-invasive treatments suggested for these patients, enhanced external counterpulsation (EECP) is considered the most effective one. EECP, administered in an outpatient setting, consists of three pneumatic cuffs applied to each of the patient’s legs that are sequentially inflated and deflated synchronised with the cardiac cycle. Numerous clinical trials have shown that EECP is safe and effective in patients with ischaemic heart disease, with or without left ventricular dysfunction, improving their quality of life. EECP appears to be beneficial as an adjunctive therapy in patients with HF of any aetiology. Cardiac syndrome X has been shown to be effectively treated with EECP. Research in EECP expanded in its potential use for entities other than heart disease. More trials are necessary, including sham-controlled trials, to further establish EECP among medical society.

Keywords: Enhanced external counterpulsation – angina pectoris – heart failure.
------------------------------------------------------------------------------------------------------------------------------
Address for correspondence: Theodoros Xanthos, University of Athens, Medical School, Department of Experimental Surgery and Surgical Research, 15B Agiou Thoma Street, 11527 Athens, Greece. E-mail: theodorosxanthos@yahoo.com
Received 9 November 2009; revision accepted for publication 14 January 2010.
Acta Cardiol 2010; 65(2): 239-247 doi: 10.2143/AC.65.2.2047060 239
---------------------------------------------------------------------------------------------------------------------------------

INTRODUCTION
Coronary artery disease (CAD) is a major medical problem with a prevalence of 213 cases for every 100,000 persons over the age of 301. Heart failure (HF) affects 1-2% of the population worldwide, and in the United States it is responsible for almost 1∞∞million hospital admissions and 50,000 deaths annually2. Despite the increasing success of conventional medical treatment
and improvement of mechanical revascularization approaches, a significant number of patients with CAD cannot be successfully managed, suffering from refractory angina pectoris (RAP)3,4. Moreover, for the group of patients with underlying HF, substantial unmet needs remain. As a result many patients are left to suffer their symptoms, restrict their activities and anticipate a reduced life expectancy5. Current non-pharmacological options for the treatment of patients with RAP, with or without underlying HF, have been suggested. Of these modalities enhanced external counterpulsion (EECP) therapy represents the most effective non-invasive echnique5,6. Furthermore, the role of EECP therapy has been recently investigated for the treatment of HF7. The aim of this review is to present the clinical applications of EECP therapy in RAP, HF and other clinical entities and to describe the group of patients who are eligible for this kind of treatment.

DESCRIPTION AND MECHANISMS OF EECP
EECP is a non-invasive procedure administered in an outpatient setting. The device consists of three pneumatic compression cuffs applied to each of the patient‘s legs - on the calves, lower thighs, upper thighs including the buttocks5,8. A computer controlled pneumatic system acts to inflate and deflate them based on the patient’s electrocardiogram(ECG).A finger plethysmogram
is used throughout treatment to monitor diastolic and systolic pressure waveforms7. A course
of EECP treatment typically involves 35 one-hour sessions, usually 5∞∞days a week over a 7-week period, though treatments twice per day have been effective as well9. The haemodynamic effects produced by EECP are similar to intra-aortic balloon pump (IABP)9. Sequential inflation of the cuffs, at the onset of diastole, produces aortic counterpulsation and an increase in diastolic pressure while rapid deflation of the cuffs, at the onset of systole, decreases systolic pressure in both the aorta and the coronary arteries10. Unlike IABP, EECP also increases venous return further, enhancing thus cardiac output10,11. Furthermore, as diastolic
inflation pressure is increased, the preload is increased, afterload is decreased, contractility is increased and mechanical efficiency is neutral12. Since shear stress is a stimulus for the release of endothelium-derived vasodilator nitric oxide as well as a modulator of the vasoconstrictor endothelin-1 release, it has been postulated that EECP, by enhancing
vascular shear stress, may favourably affect endothelial function13. Vascular mechanical forces have been suggested to initiate collateral development14. Masuda et al.15, using ammonia positron emission tomography, suggested that the development of collateral vessels is one of the mechanisms of EECP therapy. EECP was proven to exert peripheral effects similar to physical exercise16. EECP therapy exerts a ‘training’ effect decreasing thus peripheral vascular resistance and the heart rate response to exercise17. EECP effect is considered analogous to the peripheral vascular conditioning effect seen with exercise, in which improved vasomotor tone decreases the blood pressure response to exercise18. Finally, the fact that many patients experience significant symptomatic improvement, even in the absence of optimal diastolic augmentation during treatment, indicates that a placebo effect may contribute to the symptomatic benefit observed with EECP10. Evidence indicates that the use of medical devices may be associated with an enhanced placebo effect19.

EECP AND ISCHAEMIC HEART DISEASE (IHD)

The role of EECP in the treatment of IHD has been known since the early 1970s, however, it did not receive significant attention. The first pivotal turn of events came in 1999 when the Multicenter Study-EECP trial (MUST-EECP) was published1. MUST-EECP is the first prospective, randomized, blinded, placebo controlled trial that assessed safety and efficacy of
EECP after treating outpatients with angina, documented CAD and positive exercise treadmill test. The trial concluded that EECP reduces angina and extends time to exercise-induced ischaemia20. Despite the impressive results controversy and doubt remained, mostly in regard with the role placebo played in the study. A sub-study of MUST-EECP trial21 concluded that improvements on patients’ health and quality of life were present 12∞∞months after treatment with EECP. EECP was suggested as a safe treatment option for selected symptomatic percutaneous coronary intervention (PCI) candidates with obstructive CAD22. It was further suggested that EECP, as a noninvasive treatment, could be used as a first-line treatment with
invasive revascularization reserved for EECP failures, or high-risk patients23. Based on its acute haemodynamic effects, comparable to those of IABP, EECP was proposed as a potential treatment for coronary syndromes in an acute setting, as an inpatient therapy for patients with IABP contraindications24. Currently, EECP has been considered to be a more effective alternative treatment for patients with RAP who are not proper candidates for established, available non-pharmacologic options such as spinal cord stimulation25. In addition, an anti-inflammatory effect of EECP in patients with angina pectoris has been suggested when a decrease in circulating pro-inflammatory biomarker levels was demonstrated after 35 1-hour sessions26. However, in current studies, despite that endothelial improvement has been observed during the course of EECP treatment, long-term benefits of EECP could not be attributed to improved endothelial function27. Over the years, there have been many interesting
studies of EECP therapy in ischaemic heart disease summarized in table 128-41 and table 242-50,13.

EECP AND HEART FAILURE
An interesting turn in EECP research was the prescription of the technique to patients with RAP combined with left ventricular (LV) dysfunction. The primary concern of initial researchers was that the increased venous return, resulting from EECP treatment, would precipitate pulmonary oedema in these patients and might exacerbate heart failure. Nevertheless, earlier small reports demonstrated that patients with depressed ventricular function responded to treatment
with EECP considerably improving angina function and quality of life both immediately after treatment and in a 6-month follow-up51. Furthermore, benefits and safety of EECP were demonstrated to be similar in angina patients with a history of heart failure and severe systolic dysfunction with those with angina and heart failure with diastolic dysfunction25,52.
More recently, Soran e t al.53 concluded that EECP offers an effective, durable therapeutic approach for refractory angina combined with high-risk LV  dysfunction. 240 V. Kitsou et al.
Clinical applications of EECP 241

Currently, systolic blood pressure improvements have been documented during and after EECP treatment, as well as after a 6-week follow-up54. However, EECP did not improve any measurements of LV systolic or diastolic function, performed by two-dimensional and Doppler echocardiography55. Unlike the efficacy and safety of EECP treatment in RAP evidence regarding the efficacy of the procedure in patients with HF is just beginning to emerge56.
In an earlier study57, in patients with class II or III heart failure and ejection fraction less than 35%, EECP treatment was associated with a significant improvement in LV function, as measured by an increase in ejection fraction, and a significant decrease in heart rate. It was further demonstrated by later studies that EECP can be safe and well tolerated in patients with
relatively stable heart failure and no fluid overload. Also, according to a pilot study, in these patients EECP can improve exercise capacity, quality of life and functional status, both in the short term and for a period of 6∞∞months 58. Nevertheless, the results of this pilot study should be interpreted with caution given the small sample size. Nevertheless, these promising results revealed the need for a randomized control study to ascertain the efficacy of EECP as an adjunctive therapy in the management of patients with chronic stable heart failure. The Prospective Evaluation of EECP in Heart Failure (PEECH) trial concluded that EECP improved exercise tolerance, quality of life and New York Heart Association (NYHA) functional classification without an accompanying increase in peak oxygen consumption in patients with HF59,60. Futhermore, a subgroup analysis of the PEECH trial61 confirmed the beneficial  effects of EECP in elderly patients, older than 65, with chronic, stable mild-to-moderate heart failure. EECP can benefit patients with HF who already receive optimal medical therapy without achieving the desired effects. Yet, only when the haemodynamic effects of EECP during diastole and during systole are synchronised properly will the increase in venous return be compensated and not result in pulmonary congestion or even pulmonary oedema. However, while the safety of EECP in patients without significant fluid overload has been demonstrated, further studies are needed to guide the use of the technique in patients with more severe overload or acute decompensated heart failure62. EECP appears to be relatively safe in heart failure patients but the treatment‘s efficacy is more nebulous and more research is  necessary63.

PATIENT SELECTION AND LIMITATIONS
EECP is a Food and Drug Administration approved class IIb-recommended treatment for refractory angina63. Indications for EECP therapy include stable and unstable angina, class II-III stable congestive heart failure, acute myocardial infarction, and Cardiogenic shock62. As more is learned about EECP, patients once excluded from early clinical trials are now able to take advantage of EECP. Nevertheless, EECP is not suitable for some patients64,65,66 (table 3). Furthermore, another impediment to the widespread use of EECP is that many cardiologists are not fully informed about the concept of EECP as well as about the technique itself. Physicians and patients are eager to see quick results and fast improvement of their health status, whereas with EECP therapy a considerable amount of time is needed in order to observe results9.
Contraindications
Arrhythmias that interfere with machine triggering (atrial fibrillation)
Decompensated heart failure
Severe uncontrolled hypertension (> 180/110∞∞mmHg)
Cardiac catheterization or arterial puncture within 2∞∞weeks
Severe pulmonary hypertension
Severe aortic insufficiency
Severe peripheral arterial disease with rest claudication ornon-healing ulcers
Venous diseases (thrombophlebitis, deep venous thrombosis)
Bleeding diathesis or warfarin therapy
Pregnancy
Aortic aneurysm or dissection

Side effects
Skin abrasion
Haematoma of the legs
Severe pain of the legs

FURTHER CLINICAL APPLICATIONS
There has been much concern over other potential clinical applications of EECP. Kronhaus et al.67 treated with EECP 30∞∞patients with refractory angina due to cardiac syndrome X. There was a significant reduction in angina class and in inducible ischaemia. The effect Clinical applications of EECP 243 following treatment was durable, with a low incidence of recurrent angina.

Investigating the hypothesis that symptom improvement from EECP is related to improved heart rate variability (HRV).
To assess the efficacy of EECP in relieving angina and improving objective measures of myocardial ischaemia. There was no significant change in the time- or frequency-domain HRV measures after EECP.
In diabetic individuals, there was an increase in low frequency HRV, which has been associated with reduced mortality. The results of this study suggested that EECP is a safe, well tolerated, and significantly effective treatment for angina pectoris.
Improvement of endothelial dysfunction was suggested as the underlying mechanism of action; however, the efficacy of EECP in syndrome X remains unknown68.

Further studies investigate the benefits of EECP on entities other than cardiac disease. EECP improved skin oxygenation and decreased carbon dioxide load. These effects were attributed to microcirculation improvements caused by the increase of concentration and the decrease of velocity of moving blood cells observed during counterpulsation69. Also, Werner et al. used
EECP in an effort to improve renal dysfunction of liver cirrhosis. They observed that EECP improved diuresis, but did not influence the vasoconstrictive dysregulation of the kidneys in liver cirrhosis70. Furthermore, it was suggested that EECP could be a clinically useful and safe procedure in patients with acute central retinal artery occlusion or branch retinal artery occlusion71. Rajaram et al. found some patients who underwent EECP for angina or congestive heart failure who also coincidently had severe restless leg syndrome (RLS). They concluded that EECP improved RLS symptoms significantly; still, a larger number of patients should be investigated to draw further conclusions72. The effect of EECP was assessed on ischaemic
heart disease associated erectile dysfunction. Although preliminary results indicated an improvement, large scale trials and long-term data are needed73,74. An interesting study by Werner et al. Demonstrated that cerebral autoregulation ensures the constancy of cerebral blood flow even though EECP creates marked systemic changes. The decrease of blood pressure (BP) after EECP with maintained cerebral flow velocity (CBFV) indicates an improved BP/CBFV relation75.
Experimental studies have demonstrated that EECP results in endothelium-dependent vasorelaxation in the carotid arteries of hypercholesterolaemic pigs76. Furthermore,
it was suggested that  EECP does not compromise cerebral autoregulation and, therefore, does
not seem to bear cerebrovascular risks77. These data suggest that EECP might be useful in the treatment of stroke patients, as it improves neurological functional outcome78, increased power in paretic extremities and decreased spasticity79. However, randomized-controlled trials with a large sample size are needed to further define the efficacy and safety of EECP in acute stroke
management.

CONCLUSION
Safety and immediate benefits of the technique as well as the achievement of sustained symptomatic benefits and quality of life have been confirmed in most patients for up to three years80. However, patients with more severe angina and without history of HF are more likely to gain immediate symptomatic benefit whereas patients with more severe angina, diabetes,
and a history of HF are more likely to suffer from unfavourable long-term outcome and major
adverse cardiovascular events81,82. Furthermore, residual high-grade angina after EECP can occur, though uncommon, in patients with more severe angina at baseline48. More trials are necessary, including sham-controlled trials, to further establish among medical society the mechanisms, the benefits as well as the short and long-term outcome of the procedure in a variety of pathologies.
Conflict of interest: none declared.

REFERENCES
1. DeMaria A. A historical overview of enhanced external counterpulsation. Clin Cardiol 2002; 25(12∞∞suppl): II3-II5.
2. Braunwald E. Heart failure and cor pulmonale, Harrison’s principals of internal medicine - 16th edition. Edited by
Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, United States, McGraw Hill Professional,
2005:1367-78.
3. Sinvhal RM, Gowda RM, Khan IA. Enhanced external counterpulsation for refractory angina pectoris. Heart 2003; 89: 830-3.
4. Gowda RM, Khan IA, Punukollu G, Vasavada BC, Nair CK. Treatment of refractory angina pectoris. Int J Cardiol 2005; 101: 1-7.
5. Manchanda A, Soran O. Enhanced external counterpulsation and future directions: step beyond medical management for 244 V. Kitsou et al. patients with angina and heart failure. J Am Coll Cardiol 2007; 50: 1523-31.
6. Holmes DR Jr. Treatment options for angina pectoris and the future role of enhanced external counterpulsation. Clin Cardiol 2002; 25(12 Suppl 2): II22-II25.
7. Soran O. A new treatment modality in heart failure enhanced external counterpulsation (EECP). Cardiol Rev 2004; 12: 15-20.
8. Shea ML, Conti RC, Arora RR. An update on enhanced external counterpulsation. Clin Cardiol 2005; 28: 115-8.
9. Brosche TA, Middleton SK, Boogaard RG. Enhanced external counterpulsation. Dimens Crit Care Nurs 2004; 23: 208-14.
10. Bonetti PO, Holmes DR Jr, Lerman A, Barsness GW. Enhanced external counterpulsation for ischemic heart
disease: what’s behind the curtain? J Am Coll Cardiol 2003; 41: 1918-25.
11. Michaels AD, Accad M, Ports T, Grossman W. Left ventricular systolic unloading and augmentation of intracoronary pressure and Doppler flow during enhanced external counterpulsation. Circulation 2002; 106: 1237-42.
12. Michaels AD, Tacy T, Teitel D, Shapiro M, Grossman W. Invasive left ventricular energetics during enhanced external counterpulsation. Am J Ther 2009; 16: 239-46.
13. Akhtar M,Wu GF, Du ZM, Zheng ZS, Michaels AD. Effect of external counterpulsation on plasma nitric oxide and endothelin-1 levels. Am J Cardiol 2006; 98: 28-30.
14. Kersten JR, Pagel PS, Chilian WM, Warltier DC. Multifactorial basis for coronary collateralization: a complex adaptive response to ischemia. Cardiovasc Res 1999;43: 44-57.
15. Masuda D, Nohara R, Inada H, Hirai T, Li-Guang C, Kanda H, Inubushi M, Tadamura E, Fujita M, Sasayama S.
Improvement of regional myocardial and coronary blood flow reserve in a patient treated with enhanced external counterpulsation: evaluation by nitrogen-13 ammonia PET.Jpn Circ J 1999; 63: 407-11.
16. Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Kuvin JT, Schnall RP, Holmes DR, Higano ST,
Lerman A. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J Am Coll Cardiol 2003; 41: 1761-8.
17. Lawson WE, Hui JCK, Zheng ZS, Burger L, Jiang L, Lillis O, Oster Z, Soroff H, Cohn PF. Improved exercise tolerance following enhanced external counterpulsation: cardiac or peripheral effect? Cardiology 1996; 87: 271-5.
18. Stys TP, Lawson WE, Hui JCK, Fleishman B, Manzo K, Strobeck JE, Tartaglia J, Ramasamy S, Suwita R, Zheng ZS, Liang H, Werner D. Effects of enhanced external counterpulsation on stress radionuclide coronary perfusion and exercise capacity in chronic stable angina pectoris. Am J Cardiol 2002; 89: 822-4.
19. Kaptchuk TJ, Goldman P, Stone DA, Stason WB. Do medical devices have enhanced placebo effects? J Clin Epidemiol 2000; 53: 786-92. 20. Arora RR, Chou TM, Jain D, Fleishman B, Crawford L,  McKiernan T, Nesto R. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 1999; 33: 1833-40.
21. Arora RR, Chou TM, Jian D, Fleishman B, Crawford L, McKiernan T, Nesto R, Ferrans CE, Keller S. Effects of
enhanced external counterpulsation on Health-Related Quality of Life continue 12∞∞months after treatment: a sub-study  of the Multicenter Study of Enhanced External Counterpulsation. J Investig Med 2002; 50: 25-32.
22. Holubkov R, Kennard ED, Forris JM, Kelsey SF, Soran O, Williams DO, Holmes Jr. DR. Comparison of patients
undergoing enhanced external counterpulsation and percutaneous coronary intervention for stable angina pectoris.
Am J Cardiol 2002; 89: 1182-6.
23. Fitzgerald CP, Lawson WE, Hui JC, Kennard ED; IEPR Investigators. Enhanced external counterpulsation as initial revascularization treatment for angina refractory to medical therapy. Cardiology 2003; 100: 129-35.
24. Cohen J, Grossman W, Michaels AD. Portable enhanced external counterpulsation for acute coronary syndrome and Cardiogenic shock: a pilot study. Clin Cardiol2007; 30: 223-8.
25. Bondesson S, Pettersson T, Erdling A, Hallberg IR, Wackenfors A, Edvisson L. Comparison of patients undergoing enhanced external counterpulsation and spinal stimulation for refractory angina pectoris. Coron Artery Dis 2008; 19: 627-34.
26. Casey DP, Conti CR, Nichols WW, Choi CY, Khuddus MA, Braith RW. Effect of enhanced external counterpulsation on inflammatory cytokines and adhesion molecules in patients with angina pectoris and angiographic coronary artery disease. Am J Cardiol 2008; 101: 300-2.
27. Hashemi M, Hoseinbalam M, Khazaei M. Long-term effect of enhanced external counterpulsation on endothelial function in the patients with intractable angina. Heart Lung Circ 2008; 17: 383-7.
28. Lawson WE, Hui JC, Lang, G. Treatment benefit in the enhanced external counterpulsation consortium. Cardiology 2000; 94: 31-5.
29. Lakshmi MV, Kennard ED, Kelsey SF, Holubkov R, Michaels AD. Relation of the pattern of diastolic augmentation during a course of enhanced external counterpulsation (EECP) to clinical benefit (from the International EECP Patient Registry [IEPR]). Am J Cardiol 2002; 89: 1303-5.
30. Lawson WE, Kennard ED, Hui JC, Holubkov R, Kelsey SF; IEPR Investigators. Analysis of baseline factors associated with reduction in chest pain in patients with angina pectoris treated by enhanced external  counterpulsation. Am J Cardiol 2003; 92: 439-43.
31. Linnemeier G, Michaels AD, Soran O, Kennard ED; International Enhanced External Counterpulsation Patient Registry Investigators. Enhanced external counterpulsation in the management of angina in the elderly. Am J Geriatr Cardiol 2003; 12: 90-4.
32. Linnemeier G, Rutter MK, Barsness G, Kennard ED, Nesto RW; IEPR Investigators. Enhanced External Counterpulsation for the relief of angina in patients with diabetes: safety, efficacy and 1-year clinical outcomes. Am Heart J 2003; 146: 453-8.
33. Tartaglia J, Stenerson J Jr, Charney R, Ramasamy S, Fleishman BL, Gerardi P, Hui JCK. Exercise capability and myocardial perfusion in chronic angina patients treated with enhanced external counterpulsation. Clin Cardiol 2003; 26: 287-90.
34. Lawson WE, Hui JC, Barsness GW, Kennard ED, Kelsey SF; IEPR Investigators. Effectiveness of enhanced external counterpulsation in patients with left main disease and angina. Clin Cardiol 2004; 27: 459-63.
35. Henrikson CA, Chandra-Strobos N. Enhanced external counterpulsation therapy: significant clinical improvement without electrophysiologic remodelling. Ann Noninvasive Electrocardiol 2004; 9: 265-9.
36. Bagger JP, Hall RJ, Koutroulis G, Nihoyannopoulos P. Effect of enhanced external counterpulsation on dobutamineinduced left ventricular wall motion abnormalities in severe chronic angina pectoris. Am J Cardiol 2004; 93: 465-7.
37. Masuda D, Fujita M, Nohara R, Matsumori A, Sasayama S. Improvement of oxygen metabolism in ischemic myocardium as a result of enhanced external counterpulsation with heparin pretreatment for patients with stable angina. Heart Vessels 2004; 19: 59-62.
38. Michaels AD, Linnemeier G, Soran O, Kelsey SF, Kennard ED. Two-year outcomes after enhanced external counterpulsation for stable angina pectoris (from the international EECP patient registry [IEPR]). Am J Cardiol 2004; 93: 461-4.
39. Taguchi I, Ogawa K, Kanaya T, Matsuda R, Kuga H, Nakatsugawa M. Effects of enhanced external counterpulsation on hemodynamics and its mechanism. Circ J2004; 68: 1030-4.
40. Arora R, Chen HJ, Rabbani L. Effects of enhanced external counterpulsation on vascular cell release of coagulation factors. Heart Lung 2005; 34: 252-6.
41. Michaels AD, Raisinghani A, Soran O, de Lame PA, Lemaine ML, Kligfield P, Watson DD, Conti CR, Beller G.
The effects of enhanced external counterpulsation on myocardial perfusion in patients with stable angina: a multicenter radionuclide study. Am Heart J 2005; 150: 1066-73.
42. Lawson WE, Hui JC, Kennard ED, Kelsey SF, Michaels AD, Soran O; International Enhanced External Counterpulsation Patient Registry Investigators. Two-year outcomes in patients with mild refractory angina treated with enhanced external counterpulsation. Clin Cardiol 2006; 29: 69-73.
43. Loh PH, Louis AA, Windram J, Rigby AS, Cook J, Hurren S, Nikolay NP, Caplin J, Cleland JG. The immediate and long-term outcome of enhanced external counterpulsation in treatment of chronic stable refractory angina. J Intern Med 2006; 259: 276-84.
44. Nichols WW, Estrada JC, Braith RW, Owens K, Conti CR. Enhanced external counterpulsation treatment improves arterial wall properties and wave reflection characteristics in patients with refractory angina. J Am Coll Cardiol 2006; 48: 1208-14.
45. Novo G, Bagger JP, Carta R, Koutroulis G, Hall R, Nihoyannopoulos P. Enhanced external counterpulsation for treatment of refractory angina pectoris. J Cardiovasc Med 2006; 7: 335-9.
46. Soran O, Kennard ED, Kfoury AG, Kelsey SF; IEPR investigators. Two-year clinical outcomes after enhanced
external counterpulsation (EECP) therapy in patients with refractory angina pectoris and left ventricular dysfunction
(report from The International EECP Patient Registry). Am J Cardiol 2006; 97: 17-20.
47. Arora RR, Bergmann S. Effects of enhanced external counterpulsation (EECP) on myocardial perfusion. Am J Ther 2007; 14: 519-23.
48. McCullough PA, Henry TD, Kennard ED, Kelsey SF, Michaels AD. Residual high-grade angina after enhanced
external counterpulsation therapy. Cardiovasc Revasc Med 2007; 8: 161-5.
49. Michaels AD, Bart BA, Pinto T, Lafferty J, Fung G, Kennard ED. The effects of enhanced external counterpulsation on time- and frequency-domain measures of heart rate variability. J Electrocardiol 2007; 40: 515-21.
50. Yavari M, Montazeri HR. Effects of enhanced external counterpulsation on anginal symptoms and improvements in objective measures of myocardial ischaemia.Cardiovasc J Afr 2007; 18: 154-6.
51. Soran O, Kennard ED, Kelsey SF, Holubkov R, Strobeck J, Feldman AM. Enhanced external counterpulsation as treatment for chronic angina in patients with left ventricular dysfunction: a report from the International EECP Patient Registry (IEPR). Congest Heart Fail 2002; 8: 297-300.
52. Lawson WE, Silver MA, Hui JC, Kennard ED, Kelsey SF. Angina patients with diastolic versus systolic heart failure demonstrate comparable immediate and one-year benefit from enhanced external counterpulsation. J Card Fail 2005; 11: 61-6.
53. Soran O, Kennard ED, Kfoury AG, Kelsey SF. Refractory angina pectoris and left ventricular dysfunction (report from the international EECP patient registry. Am J Cardiol 2006; 97: 17-20.
54. Campbell AR, Satran D, Zenovich AG. Enhanced external counterpulsation improves systolic blood pressure in patients with refractory angina. Am Heart J 2008; 156: 1217-22.
55. Kumar A, Aronow WS, Vadnerkar A, Sindhu P, Mittal S, Kasliwal RR, Trehan N. Effect of enhanced external counterpulsation on clinical symptoms, quality of life, 6-minute walking distance, and echocardiographic measurements of left ventricular systolic and diastolic function after 35∞∞days
of treatment and at 1-year follow up in 47∞∞patients with chronic refractory angina pectoris. Am J Ther 2009; 16:
116-8.
56. Blazing MA, Crawford LE. Enhanced external counterpulsation (EECP): Enough evidence to support this and the next wave? Am Heart J 2003; 146: 383-4.
57. Gorscan J III, Crawford L, Soran O, Wang H, Severyn D, de Lame PA, Schneider V, Feldman AM. Improvement in left ventricular performance by enhanced external counterpulsation in patients with heart failure. J Am Coll Cardiol 2000; 35(2 Suppl A): 230A: 901-5.
58. Soran O, Fleishman B, Demarco T, Grossman W, Schneider VM, Manzo K, de Lame PA, Feldman AM. Enhanced external counterpulsation in patients with heart failure: a multicenter feasibility study. Congest Heart Fail 2002; 8: 204-8.
59. Feldman AM, Silver MA, Francis GS, De Lame PA, Parmley WW. Treating heart failure with enhanced external
counterpulsation (EECP): Design of the prospective evaluation of EECP in heart failure (PEECH) trial. J Card Fail
2005; 11: 240-5.
60. Feldman AM, Silver MA, Francis GS, Abbottsmith CW, Fleishman BL, Soran O, de Lame PA, Varricchione T;
PEECH Investigators. Enhanced external counterpulsation improves exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol 2006; 48: 1198-205.
61. Abbottsmith CW, Chung ES, Varricchiose T, de Lame PA, Silver MA, Francis GS, Feldman AM. Prospective evaluation of EECP in congestive heart failure investigators. Enhanced external counterpulsation improves exercise duration and peak oxygen consumption in older patients with heart failure: a subgroup analysis of the PEECH trial. Congest Heart Fail 2006; 12: 307-11.
62. Silver MA. Mechanisms and evidence for the role of enhanced external counterpulsation in heart failure management. Curr Heart Fail Rep 2006; 3: 25-32.
63. Arora RR, Shah AG. The role of enhanced external counterpulsation in the treatment of angina and heart failure. Can J Cardiol 2007; 23: 779-81.
64. Lawson WE. Current use of enhanced external counterpulsation and patient selection. Clin Cardiol 2002; 25
(12 Suppl 2): II16-II21.
65. Michaels AD, McCullough PA, Soran OZ, Lawson WE, Barsness GW, Henry TD, Linnemeier G, Ochoa A, Kelsey SF, Kennard ED. Primer: practical approach of patients for 246 V. Kitsou et al. and application of EECP. Nat Clin Pract Cardiovasc Med 2006; 3: 623-32.
66. Werner D, Kropp J, Schellong S, Friedel C, Voigt JU, Ludwig J, Daniel WG, Flachskampf FA. Practicability and
limitations of enhanced external counterpulsation as an additional treatment for angina. Clin Cardiol 2003; 26:
525-9. 67. Kronhaus KD, Lawson WE. Enhanced external counterpulsation is an effective treatment for syndrome X. Int JCardiol 2009; 135: 256-7.
68. Celik T, Iyisoy A, Yuksel UC, Amasyali B. A new treatment modality in management of patients with cardiac syndrome X: Enhanced external counterpulsation. Int J Cardiol 2008 Dec 29 [Epub ahead of print].
69. Hilz MJ, Werner D, Marthol H, Flachskampf FA, Daniel WG. Enhanced external counterpulsation improves skin oxygenation and perfusion. Eur J Clin Invest 2004;34: 385-91.
70. Werner D, Tr├Ągner P, Wawer A, Porst H, Daniel WG, Gross P. Enhanced external counterpulsation: a new technique to augment renal function in liver cirrhosis.Nephrol Dial Transplant 2005; 20: 920-6.
71. Werner D, Michalk F, Harazny J, Hugo C, Daniel WG, Michelson G. Accelerated reperfusion of poorly perfused
retinal areas in central retinal artery occlusion and branch retinal artery occlusion after a short treatment with enhanced external counterpulsation. Retina 2004; 24: 541-7.
72. Rajaram SS, Shanahan J, Ash C, Walters AS, Weisfogel G. Enhanced external counter pulsation (EECP) as a novel treatment for restless legs syndrome (RLS): a preliminary test of the vascular neurologic hypothesis for RLS. Sleep Med 2005; 6: 101-6.
73. El-Sakka A, Morsy A, Fagih B. Enhanced external counterpulsation in patients with coronary artery disease-associated erectile dysfunction. Part I: effects of risk factors. J Sex Med 2007; 4: 771-9.
74. El-Sakka AI, Morsy AM, Fagih BI. Enhanced external counterpulsation in patients with coronary artery diseaseassociated erectile dysfunction. Part II: impact of disease duration and treatment courses. J Sex Med 2007; 4: 1448- 53.
75. Werner D, Marthol H, Brown CM, Daniel WG, Hilz MJ. Changes of cerebral blood flow velocities during enhanced external counterpulsation. Acta Neurol Scand 2003;107: 405-11.
76. Tao J, Tu C, Yang Z, Zhang Y, Chung XL, Ma H, Zhen ZS. Enhanced external counterpulsation improves endothelium dependent vasorelaxation in the carotid arteries of hypercholesterolemic pigs. Int J Cardiol 2006; 112: 269-74.
77. Marthol H, Werner D, Brown CM, Hecht M, Daniel WG, Hilz MJ. Enhanced external counterpulsation does not compromise cerebral autoregulation. Acta Neurol Scand 2005; 111: 34-41.
78. Han JH, Leung TW, Lam WW, Soo YO, Alexandrov AW, Mok V, Leung YF, Lo R,Wong KS. Preliminary findings of external counterpulsation for ischemic stroke patient with large artery occlusive disease. Stroke 2008; 39: 1340-3.
79. Han JH, Wong KS. Is counterpulsation a potential therapy for ischemic stroke? Cerebrovasc Dis 2008; 26: 97-105.
80. Loh PH, Cleland JG, Louis AA, Kennard ED, Cook JF, Caplin JL, Barsness GW, Lawson WE, Soran OZ, Michaels AD. Enhanced external counterpulsation in the treatment of chronic refractory angina: a long-term follow-up outcome from the International Enhanced External Counterpulsation Patient Registry. Clin Cardiol 2008; 31: 159-64.
81. Lawson WE, Hui JC, Kennard ED, Barsness G, Kelsey SF. Predictors of benefit in angina patients one year after completing enhanced external counterpulsation: initial responders to treatment versus nonresponders. Cardiology 2005; 103: 201-6.
82. Lawson WE, Kennard ED, Holubkov R, Kelsey SF, Strobeck JE, Soran O, Feldman AM. Benefit and safety of
enhanced external counterpulsation in treating coronary artery disease patients with a history of congestive heart
failure. Cardiology 2001; 96:78-84.
Clinical applications of EECP 247