illustrative embodiments of the preferred embodiment are described below . in the interest of clarity , not all features of an actual implementation are described in this specification . it will of course be appreciated that in the development of any such actual embodiment , numerous implementation - specific decisions must be made to achieve the developer &# 39 ; s specific goals , such as compliance with system - related and business - related constraints , which will vary from one implementation to another . moreover , it will be appreciated that such a development effort might be complex and time - consuming but would nevertheless be a routine undertaking for those of ordinary skill in the art having the benefit of this disclosure . in the specification , reference may be made to the spatial relationships between various components and to the spatial orientation of various aspects of components as the devices are depicted in the attached drawings . however , as will be recognized by those skilled in the art after a complete reading of the present application , the devices , members , apparatuses , etc . described herein may be positioned in other desired orientations . thus , the use of terms to describe a spatial relationship between various components or to describe the spatial orientation of aspects of such components should be understood to describe a relative relationship between the components or a spatial orientation of aspects of such components , respectively , as the device described herein may be oriented in any desired direction . the system and method in accordance with the present application overcomes one or more of the above - discussed problems commonly associated with conventional methods for the treatment of endothelial dysfunction . it is designed to treat endothelial dysfunction through activation of the paracrine and autocrine processes in the endothelium by creating endothelial mechanotransduction . the process involves providing electrical stimulation to skeletal muscles over large areas of the body with multiple treatment pads that are sequentially initiated in overlapping intervals to elevate blood flow and venous return . this increased blood flow creates increased frictional drag on the endothelial wall between blood cells and the endothelial wall itself . this laminar shear stress directly applied to the endothelial wall creates mechanotransduction . through mechanotransduction , the autocrine / paracrine functions of the endothelial cells increase the production of vasoactive substances including nitric oxide , prostacyclin , sod and many others . this process avoids invasive procedures and the risks associated with drugs . these and other unique features of the device are discussed below and illustrated in the accompanying drawings . the system and method will be understood , both as to its structure and operation , from the accompanying drawings , taken in conjunction with the accompanying description . several embodiments of the system may be presented herein . it should be understood that various components , parts , and features of the different embodiments may be combined together and / or interchanged with one another , all of which are within the scope of the present application , even though not all variations and particular embodiments are shown in the drawings . it should also be understood that the mixing and matching of features , elements , and / or functions between various embodiments is expressly contemplated herein so that one of ordinary skill in the art would appreciate from this disclosure that the features , elements , and / or functions of one embodiment may be incorporated into another embodiment as appropriate , unless otherwise described . the system and method of the present application is illustrated in the associated drawings . the assembly includes a controller , such as a waveform generating device . the controller induces an electrical current through a plurality of treatment pads coupled to a human body . the treatment pads are sequentially initiated by the controller in short overlapping periods . the electrical stimulation causes contractions which will directly compress the venous system . by way of the one - way valves in the veins , the sequential stimulation pumps the blood toward the heart . referring now to the drawings wherein like reference characters identify corresponding or similar elements in form and function throughout the several views . fig1 illustrates the general configuration of the electrical stimulation system 101 . system 101 includes controller 40 having a plurality of leads 42 that are connected together via treatment pads 44 . treatment pads 44 are configured for attachment to the human body . a plurality of pads 44 are coupled along the same vein in a predetermined pattern . the pads 44 / leads 42 are used to conduct the waveforms into and through the tissue being treated . knobs 41 are also included and serve as a means of controlling the intensity of the waveform transferred through pads 44 . an operator is able to regulate the waveform as needed . controller 40 is operated by electrical power provided through a power source . as seen in fig1 , a plug 48 and power cord 46 may be included . system 101 is configured to receive power from the power source and transmit an electrical stimulation signal through leads 42 to the skeletal muscles of the human body . each vein is surrounded by muscles that , when stimulated , apply pressure directly to the veins in the same way the body normally does to move blood . system 101 is not limited to a particular power source or voltage . an example is an 18 - volt power source . controller 40 is configured to process and regulate the timing and sequence of electrical stimulations . this may be done via a processing unit and a plurality of controlling devices , such as a timer , a rheostat , and a gating device for example . controller 40 controls the duration , intensity , and sequence of the waveform . controller 40 is configured to regulate the intervals of treatment at pads 44 . the length of time may be limited to one half second , up to a plurality of seconds for example . it is understood that system 101 may include any number of leads 42 and pads 44 . furthermore , pads 44 may be releasably coupled to the human body using methods common in the industry . such methods may include , but are not limited to the use of adhesives , manual straps , hook and loop fasteners , elastic , and other garments . each is configured to hold pads 44 in place during treatment . additionally , although a wire lead has been described , the leads may use technology to permit wired and / or wireless methods of electrical transmission . system 101 uses neuromuscular stimulation applied at multiple locations on any and all extremities of the human body to contract skeletal muscles in a sequential pattern , beginning from a distal location to a proximal location on the extremity . this increases the blood flow to the heart thereby instigating more frictional drag between blood cells and the endothelial layer . the shear stress produces increased mechanotransduction activating the paracrine and autocrine processes listed above . referring now also to fig2 in the drawings , a view showing the cellular basis of mechanotransduction is illustrated . as stated previously , the contraction of the skeletal muscles directly compresses the blood vessels in the body , causing increased blood flow in the blood vessels . blood 70 flows through the blood vessels in a laminar fashion , meaning that blood in the center flows more rapidly than the blood adjacent to the endothelial cells 72 of the lining within the blood vessel . the flow is varied due to the frictional forces . these frictional forces create shear stress on the endothelial cells 72 . shear stress transduces the stresses into chemical signals 73 . these chemical signals 73 travel through a calcium pathway to activate endothelial nitric oxide synthase ( enos ) which synthesizes citruline and nitric oxide ( no ) from l arginine . some of the no immediately migrates into the smooth muscle cells 74 where it converts guanosine triphosphate into cyclic guanosine monophosphate . the cyclic guanosine monophosphate causes relaxation in the smooth muscle cells resulting in vasodilation . the balance of the no , and other secretagogues , migrate into the veins and arteries . referring now also to fig3 and 4 in the drawings , a representative side view of a blood vessel using system 101 is shown . as seen in fig3 , electrical stimulation causes the skeletal muscles 57 to contract ( see arrows 58 a ) which compresses the vein 50 . this compression forces the blood 56 both proximally and distally , thereby closing the distal one - way valve 54 b and leaving open only the proximal valve 54 a . this forces the blood 56 into the next proximal segment of the vein . as seen in fig4 , as the stimulation ends , the muscles 57 relax ( see arrows 58 b ) which enlarges the vein 50 , creating a negative hydraulic pressure which causes the proximal valve 54 a to close and the distal valve 54 b to open , drawing blood 56 from the next distal segment of the vein . referring now also to fig5 in the drawings , a front view of a human body illustrating exemplary placement of treating pads 44 as used with system 101 is illustrated . each pad 44 is in electrical communication with controller 40 . the pads 44 are routed so as to follow a continuous vein path back to the heart . a first route is seen in the right leg of the body and a second route is seen in the left leg of the human body . each route is regulated through controller 40 . each route may be regulated simultaneously or independently . additionally , the stimulation of the skeletal muscles within each route may be stimulated either simultaneously or independently between the routes . the pads 44 are arranged in pairs wherein each treatment pair is aligned in approximately 180 degree opposed placement relative to one another . referring now also to fig6 in the drawings , a flowchart of the method of using system 101 with its therapeutic effects is illustrated . chart 201 shows the sequence of actions which occur during use of system 101 and the possible therapeutic consequences which result from the application of the present invention to a human subject . as seen in chart 201 , controller 40 selectively provides electrical stimulation to leads 42 through pads 44 which thereby contracts the skeletal muscles . this contraction increases the blood flow in the veins which thereby does at least 2 things : ( 1 ) increases laminar stresses to induce endothelial mechanotransduction ; and ( 2 ) increases the delivery of o 2 and other nutrients to the body by way of the capillaries . the benefits of each is therein illustrated in chart 201 . this is a unique application method for neuromuscular electrical stimulation requiring the chronic ( at least 30 - days duration ) application of treatments over a large area of the body ( all four extremities is the preferred embodiment ), and by the overlapping , sequential method in order to create endothelial mechanotransduction at a sufficient magnitude to reach therapeutic levels of vasoactive substances . the nature and magnitude of shear stress and mechanotransduction play an important role in long - term maintenance of the structure and function of the blood vessel and is an important modulator of cellular function in the cardiovascular system . data suggests that laminar shear stress stimulates cellular responses that are essential for endothelial cell function and are atheroprotective . shear stress has an effect on endothelial - mediated alterations in coagulation , leukocyte and monocyte migration , smooth muscle growth , lipoprotein uptake and metabolism , and endothelial cell survival . endothelial cell response to shear stress includes mechanotransducers ( integrins , caveolae , ion channels , and g proteins ), intermediate signaling molecules ( c - src , ras , raf , protein kinase c ), the mitogen activated protein kinases ( erk1 / 2 , jnk , p38 , bmk - 1 ), and the production of nitric oxide ( no ), prostacyclin , aldose reductase and many other vasoactive substances . as a result of their unique location , endothelial cells experience three primary mechanical forces : ( 1 ) pressure , created by the hydrostatic forces of blood within the blood vessel ; ( 2 ) circumferential stretch or tension , created as a result of defined intercellular connections between the endothelial cells that exert longitudinal forces on the cell ; and ( 3 ) shear stress , the dragging frictional force created by blood flow . of these forces , shear stress is a particularly important hemodynamic force because it stimulates mechanotransduction and the release of no and other vasoactive substances , changes gene expression , cell metabolism , and cell morphology . no is a versatile and powerful molecule . it plays a fundamental role in controlling a range of simple bodily functions such as circulation of the blood , activities of the brain , lungs , liver , stomach , kidneys , genitals and other organs . it works in relaxing vascular and non - vascular smooth muscle cells , increasing local blood flow , decreasing local inflammation , inhibiting platelet aggregation and smooth muscle cell proliferation , reducing expression of cell surface adhesion proteins , and controlling neurotransmission . the lack of shear stress leads to a lack of bioavailability of no , a condition commonly called endothelial dysfunction , and this may provide a mechanism by which risk factors such as hypertension , diabetes , hypercholesterolemia , and sedentary lifestyle act to promote atherosclerosis . endothelial dysfunction is recognized as a significant health risk which contributes to atherosclerosis , hypertension , heart failure , vasculitis and diabetes . use of system 101 results in responses that range from instantaneous ion fluxes and biochemical pathways to gene and protein expression . through the process of endothelial mechanotransduction , elevated levels of several substances , including nitric oxide , prostacyclin , thrombomodulin , superoxide dismutase , glutathione , krupple - like factor 2 , endothelial progenitor cells , and many others are created or elevated . this combination of increased blood flow ( bringing nutrients and oxygen to the tissue ) and the therapeutic effects of shear stress , mechanotransduction and the vasoactive substances have wide application and the potential to improve many serious ailments . treatment will be given to both lower and upper extremities to have whole - body benefits . treatment begins by placing treatment pads on the patient in such a manner as to treat in sequential order beginning at the most distal portion with succeeding treatment pads placed proximally on the body . while there are generalized placement parameters , exact placement depends upon the condition being treated and the physiology of the patient . pads 44 may be placed in anterior - posterior opposition or bilaterally , or other angles which may prove effective . once the pads 44 are in place , the operator initiates transmittal of waveforms through the pads 44 to the tissue . beginning with the most distal pair of treatment pads on one extremity then moving to the next proximal pair of treatment pads , then the next , continuing in like manner until all pads on that extremity are gradually adjusted upward in intensity and the patient &# 39 ; s comfort level is broached , then the intensity is slightly reduced . each successive set of treatment pads is adjusted in like manner until all treatment pads are receiving waveforms just below the outer limits of the patient &# 39 ; s comfort zone . after one side of the body has all treatment pads adjusted , proceed to the contralateral extremity and repeat the same sequence of adjustments . once all treatment pads are receiving waveforms , it may be necessary to adjust the intensity of some or all of the treatment pads . during the course of treatment , it will be necessary to adjust the intensity up or down ( titration ) as the patient becomes adjusted to the treatment , or as the nerves become more sensitive to stimulation . the preferred level of treatment is just below the patient &# 39 ; s maximum tolerance level . the treatment will normally last about one hour , but there may be situations where more or less time will be indicated . an example of a possible treatment regimen is to have 3 to 5 treatments a week for 4 to 8 weeks . it is essential that the overall treatment be administered chronically to achieve the full therapeutic benefits . one such desired benefit is the development of collateral circulation which will continue to contribute to blood flow after completion of the course of treatments . referring now also to fig7 in the drawings , a more detailed exemplary side view of a human leg showing the pads 44 ( denoted by the circled numbers 1 , 2 , 3 , and 4 ) aligned with a particular vein . as seen , the muscles are selectively contracted and released at each location on the extremity . referring now also to fig8 in the drawings , the sequential nature of system 101 is shown in more clarity . fig8 shows a single vein having a plurality of muscles 57 a / 57 b with a plurality of valves 54 a / 54 b . the vein is illustrated in four sequences . each sequence is used to show the operation of controller 40 to induce proper blood flow . in sequence 1 , muscle 57 a is contracted through electrical stimulation via one or more leads at a particular location on the body . the contraction of those muscles pushes blood out both proximally and distally , thereby closing the distal one - way valve 54 b and leaving open only the proximal valve 54 a ( see also fig3 and 4 ). this forces the blood 56 into the next proximal segment of the vein . the valves in all the proximal segments are open to permit blood flow . while muscles 57 a remain contracted , muscles 57 b are then also contracted as seen in sequence 2 . by maintaining the contraction of muscles 57 a while next stimulating the contraction of muscles 57 b , the blood is ensured to continue flowing to the next proximal segment . the process continues through the remaining sequential steps ( sequence 3 and 4 ) until all leads in on the vein have been stimulated . the process of maintaining at least two neighboring stimulated muscles at a single time is important . as seen in fig8 , system 101 may be configured to sequentially stimulate all muscles in order without the release of any prior muscles until the entire vein has been stimulated . for example , system 101 could be configured to maintain the stimulation of the muscles in sequential order from muscles 57 a through each set of muscles until the final set are stimulated ( illustrated in sequence 4 ). it is understood that system 101 may also be configured to selectively cease stimulation of particular muscle groups during the entire sequence . for example , once muscles 57 c are stimulated , controller 40 destimulates muscles 57 a . with either of the stimulation methods above , once the last muscle group is stimulated , the entire sequence is started over . this repeats itself for a predetermined time frame for each treatment session . the current application has many advantages over the prior art including at least the following : ( 1 ) improves endothelial dysfunction through activation of the endocrine , paracrine and autocrine processes in the endothelium ; ( 2 ) treating large areas of the body with multiple treatment pads using sequential overlapping intervals of contractions from distal to proximal so as to elevate blood flow and venous return ; ( 3 ) increase laminar shear stress to trigger endothelial mechanotransduction ; and ( 4 ) providing the benefits of endogeneous no ( and many other helpful vasoactive substances ) and the restoration of endothelial function without the disadvantages and potential side effects of drug use . the particular embodiments disclosed above are illustrative only , as the application may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein . it is therefore evident that the particular embodiments disclosed above may be altered or modified , and all such variations are considered within the scope and spirit of the application . accordingly , the protection sought herein is as set forth in the description . it is apparent that an application with significant advantages has been described and illustrated . although the present application is shown in a limited number of forms , it is not limited to just these forms , but is amenable to various changes and modifications without departing from the spirit thereof .
a method and system for creating shear stress and endothelial mechanotransduction through neuromuscular stimulation of the muscle pump . chronic application a minimum of 30 days triggers the autocrine and paracrine processes which elevates production of vasoactive substances including nitric oxide , prostacyclin , superoxide dismutase , thrombomodulin , glutathion , krupple - like factor 2 and many others . chronic application also promotes angiogenesis and development of collateral circulation . this is a cost - effective , non - invasive , drug - free therapy to treat vascular dysfunction and ameliorate or reverse its effects on cardiovascular health .