Perspectives in Circulation Today

Dear Circulator Boot Customers,

Included below is the most recent edition of Perspectives in Circulation Today. This edition continues the focus on Endothelium with an assessment of recent studies on its ability to respond to various physiological and pharmaceutical stimuli. The discussion incorporates contemporary learning in suggesting a protocol for using Circulator Boot therapy to offset the initial detrimental effects of exercise regimens often used for Claudicators.

There are a few new developments to report from our headquarters. Please welcome Jack May and Larry Hutchison. Larry and Jack have an impressive track record of leading companies through high growth life cycles and have recently assumed day-to-day responsibilities for the company. They have hit the ground running and already instituted several exciting new programs for our customers and prospects.

Please join us at the April, APWCA Conference in Philadelphia. Stop by the booth and say hello or attend our session, Pneumatic Venous & Arterial Therapy to be held on Thursday April 2nd from 12:00 - 2:00.

Keep up the good pumping and hope to see you in April.

Richard S Dillon, MD, FACP, FACE, FSVMB, FACA, FAPWCA
Director, Clinical Affairs Circulator Boot Corporation

Significance of Tests of Endothelial Function

Booting Safer than Exercise for Claudicators?

In a previous Newsletter titled The Endothelium: An Organ with Many Special Functions, the many functions of the Endothelium were briefly discussed. The classic role as a container of the blood volume and a biocompatible barrier between the blood and tissues was expanded to include its function as a selective filter for leukocytes, gases and macromolecules. More recently its response to neural and humoral signals and its elaboration of nitric oxide, prostacyclin, fibrinolysins and endothelial growth factors has been appreciated. Tests of endothelium function in its ability to respond to both physiological and pharmaceutical stimuli have been the subject of many recent publications (Table 1).

Table 1: Tests of Endothelial Function

Vascular Bed	Technique	Means to Stimulate Response
Coronary Arteries
	Quantitative Coronary Angiography	Response to Acetylcholine, bradykinin or serotonin
	Intracoronary Doppler	Response to acetylcholine, bradykinin or serotonin
Peripheral Arteries
Brachial artery	Forearm occluded by cuff for 5 minutes	Reactive hyperemia, shear stress, nitric acid release, "Flow-mediated vasodilatation" or "FMD"
Microcirculation	Forearm venous pletysmography, digital photopletysmography or skin laser Doppler	Reactive hyperemia

By a variety of mechanisms (Table 2), abnormalities in the tests of endothelium function have been associated with increased morbidity and mortality due to arteriosclerotic diseases and microvascular diseases. While there are multiple means to measure endothelial function, the Flow Mediated Dilation Test (FMD) has been popular as it is noninvasive and readily performed by a skillful ultrasound technician. Kuvin et al (2007), for example, found the FMD test highly predictive of coronary heart disease with an odds ratio of 1:32 for each percentage point decrease in FMD. A FMD >=10% had a negative predictive value over 95% while a FMD under 10% had a 91% sensitivity in predicting coronary disease. Again, Malecki et al (2008) found FMD dysfunction (and carotid intima-media thickness) to be associated with diabetic retinopathy in type 2 diabetics.

Table 2: Pathological Associations of Endothelial Dysfunction

Vasoconstriction	Vascular inflammation	Platelet activation	Leukocyte adherence	Arteriosclerosis
Mutogenesis	Pro-oxidation	Thromboses	Impaired coagulation	Decreased angiogenesis

In general, the FMD test results are related to health and physical fitness. Active fit subjects do well while obese, diabetic, hypertensive subjects do not. One of the main mechanisms of endothelial dysfunction is the diminishing of nitric oxide, often due to high levels of asymmetric dimethylarginine(ADMA), which interfere with the normal L-arginine-stimulated nitric oxide synthesis. At present no reliable means is available to control ADMA and its detrimental effects on health. In addition to being the main determinant of basal vascular smooth muscle tone, NO acts to negate the actions of potent endothelium-derived contracting factors such as angiotensin II and endothelin-1. In addition, NO serves to inhibit platelet and white cell activation and to maintain the vascular smooth muscle in a nonproliferative state.

Joras and Poredos (2008) noted the literature on the deterioration of FMD after exercise in claudicators, and extended observations on diminished FMD to 4 hours after treadmill training. The decrease in FMD suggests that harmful mediators are released into the general circulation from ischemic tissue after each exercise-induced ischemic episode (see Brevetti et al: Exercise increases soluble adhesion molecules ICAM-1 and VCAM-1 in patients with intermittent claudication. Clin Hemorheol Microcirc 24: 193-9, 2001.) Exercise therapy is not without potential risk and harm, the earlier training episodes perhaps more risky than later ones. In contrast to the acute detrimental effects of exercise in claudicators, Bonetti et al (2003) found that external counterpulsation improved endothelial function after the first treatment and continued to do so in the middle and at the end of a course of treatments with the effect lasting at the time of one month follow-up. Schecter (2003) likewise found a course of 35 external counterpulsation (ECP) treatments to be associated with significant increases in FMD in patients with inoperable refractory angina pectoris. Beneficial results, however, may also be found with exercise after long term rehabilataion programs. Walter et al (2004)were able to show that a schedule of exercise 6 times daily for 4 weeks in the hospital significantly improved endothelial function in the internal mammary artery after a acetylcholine challenge in patients with stable coronary disease. Fuchsjager et al (2002) showed a bicycle exercise program significantly increased both FMD and peak oxygen uptake for the duration of the program; benefit was lost after cessation of regular exercise. The benefits of exercise programs for those capable enrolling in them may include superior event-free survival at half the cost versus percutaneous coronary angioplasty in patients with stable coronary heart disease (Hambrecht et al 2004) and in patients with advanced CHF (NYHA class III), an enhanced physical work capacity, an improvement in stroke volume and a reduction in cardiomegaly (Erbs et al 2003). Patients incapable of an exercise program due to rest pain or advanced heart failure may become capable of doing so after a course of Circulator Boot therapy.

Table 3: Effect of Therapies on FMD

Patient Category	Treatment	Effect on FMD
Intermittent Claudication	Treadmill Exercise	Initially a significant decrease up to 4 hours - A significant increase after long term exercise program.
Coronary heart disease	External Counterpulsation	Significant increase after first treatment and further benefit after a course of 35 treatments