“Flow and Rate”: Concept and Clinical Applications of a New Hemodynamic Theory

". . . From the heart arise the vessels which go to the whole body . . . if the physician lay the hands or his fingers to the head, to the back of the head, to the hands, to the place of the stomach, to the arms or to the feet, then he examines the heart, because all his limbs possess its vessels, that is: the heart speaks out of the vessels of every limb . . . If the heart trembles, has little power and sinks, the disease is advancing.” The Papyrus Ebers, c. 1534 BC (Stern,1875).

1. The left heart circuit: it is characterized anatomically, by two high remodeling zones that represent the main circulatory pumps: the left ventricle (LV) and the aorta with the Valsalva as been shown on (Table1) and ( Figure 2). Flow dynamics inside the Valsalva sinuses determines coronary ostia morphogenesis (Hutchins, 1988) and may contribute to a severe hemodynamic deterioration (Palmieri, 2001). So a shear stress-mediated endothelial function must be induced at the left heart side according to the Newton's principles by maintaining a physiological arterial pulse pressure (Feynman, et al., 2005). The LV almost, triples its myocardial mass during the first postnatal month with an important arterial angiogenesis. (Kozák-Bárány, 2001). According to Laplace's law, this LV remodeling could be enhanced by the posterior location of the LV (behind the RV), less limited by the pericardium and sternum, which increases the gravity effect, particularly in the neonatal supine position. The LV remodeling will be continued and maintained later on, influenced by ESS, the spherical shape of the LV (Yacoub, 1995), the elevated vascular resistances and the gravity effect at the aortic root. Disturbed flow dynamics at the left heart side induce atherosclerotic lesion (Samady, et al. 2011)), which is uncommon at the right heart side pulmonary arterial walls, most probably due to the constant delivery of ESS by the respiratory pump.  Laplace  posterior to RV less restricted by the pericardium;  Newton  spherical shape (Tumkosit M 2007);  resistances.

Z2 Aorta + Valsalva High
 Shear stress (Newton): peristaltic pump + gravity effect at the Valsalva;  Laplace (less restricted external sheath at the arch),  resistances. 2. The right heart circuit: contrarily to the left, the right heart could adjust blood volume and shear rates at 5 different anatomical zones according to its physiological demands. In antenatal period, the right heart receives and pumps in equal rates more volume than the left, but keeps low remodeling due to pressure release through physiological shunts (Clark, 1987). After birth and shunts closure, both right and left ventricles share equal volume and rate inducing equal pulmonary and systemic cardiac output (CO), but remodeling remains inferior at the right heart side most probably due to venous steady flow and ventricular wall trabeculae. As shown in (Table 2) and (Figure 2), it could be identified by five different remodeling zones . Normally, the respiratory pump increases shear rates at the pulmonary endothelium externally creating an indirect or reversed pulse pressure shear stress (Newton). But with zones of steady flow and others with low pulse pressure the situation becomes more complex with physics laws applications. In fact, both Bernoulli (Calvert, 2000), and Newton in addition to the gravity effect of Pascal's law as well (Humbert, 1947), must be considered to deliver a shear stress-mediated endothelial function. Most importantly, the delivery of ESS with a CAD should be induced without disturbing the physiological remodeling of the right heart circuit (Buckberg, 2006). Direct induction of shear stress according to Newton's law like with an intravenous or intrapulmonary pulsatile perfusion must be avoided as it could induce serious hemodynamic conditions such as an irreversible pulmonary remodeling such us the Eisenmenger syndrome (D'Alto M, et al., 2007) or coronary bypass venous grafts disease. Also, the RV is preload dependant, that could not tolerate to be unloaded  3. Hemorheological stock: the right heart circuit contains > 64% of blood volume surrounded by an important mass of endothelial cells. This natural stock of blood volume and endothelial mass can be stimulated by a proper pulsatile CAD, adaptable for right heart circuit's biophysics and physiopathology, for inducing shear stress-mediated endothelial function enhancement. Contrarily, to current evidence of high mortality of CHF patients associated with right heart failure (Haddad, 2011), the concept of the present therapeutic approach considers the right heart as a physiological backup for management of almost all types of hemodynamic and circulatory disorders, including CHF patients ). As been demonstrated on (Table 3), the right heart afterlaod could improve or deteriorates the global cardiac output (CO) and hemodynamic, for example nitrates therapies that could improve left ventricular MI by lowering the systemic afterload, may worsen and be fatal in case of RV ischemia (Haji, 2000).  Table 3. Dominancy of the right heart over the left heart through pulmonary vascular resistances :1= i.e. nitrates therapy in right ventricular ischemia; 2= i.e. epinephrine therapy with cyanotic spells (creating an indirect internal pulse pressure closer to Newton's law). Another example is observed in patients in squatting position during cyanotic spells of Tetralogy of Fallot (TOF) that increases the systemic vascular resistances (Senzaki, 2008) and increases the intrapulmonary flow and shear rates in a retrograde manner through the malaigned VSD to lower the pulmonary vascular resistances, followed by global hemodynamic improvement. The increased intrapulmonary shear rate that can be induced by adrenaline injection as well during the cyanotic TOF spells (Table 3), provides shear stress-mediated endothelial function approaching Bernoulli's law. Reduction of pulmonary vascular resistances is an immediate target for hemodynamic improvement that can be achieved by shear stress-mediated endothelial function enhancement directly with an intrapulmonary shear rate enhancement device (e.g. pulsatile catheter); or indirectly with an external pulsatile device (e.g. pulsatile suit). 5. Microcirculation: as is known, human being is a multicellular organism in which cellular biology performs a main role in terms of development, maintenance, proper operation and also failure of vital organs (Vincent, 2008). Maintaining good operation of organs by means of microcirculation in the organ constitutes a characteristic effect of the proposed concept. Microcirculations are controlled by plurality of endothelial mediators of vasodilators, which are dependent on shear stress (Koller, 1993) (Poelmann, 2008). Under normal hemorheological condition, microcirculation behavior approaches that of Newton's law. A symbolic example observed in athletics, high physical performance, which means shear stress-mediated endothelial function, could be achieved with slow heartbeat (shear rate) and increased stroke volume (pulse pressure). In contrast, in any abnormal hemorheological state, microcirculation presents behavior that approaches that of Bernoulli's law, as interpreted by the Fahraeus-Lindqvist effect in which plasma stuck at the inner vascular boundary layers while erythrocytes move faster at the center (Fahraeus & Lindqvist, 1931;Neri Serneri, 1981). This could explain absence of cyanosis in anemic patients with low hematocrite, unlike those patients with high hematocrite, as erythrocytes aggregations at microcirculations induce cyanosis with clinical signs finger clubbing (drumsticks fingers).

Cardiovascular pathogenesis
Endothelial dysfunction is responsible for almost all types of cardiovascular pathogenesis whatever congenital or acquired (Endemann et al., 2004) The dependency of the endothelium on shear stress stimuli starts by the placental angiogenesis since the 6 th gestational day, once there are normal hemorheolgical maternal factors (Heilmann, et al, 2005). Troubled shear stress forces due to an increased blood pressure (e.g.,preeclampsia) or low hematocrit (anticoagulant drugs), induces congenital anomalies and could interrupt the course of pregnancy (Aron, et al., 2003).
By the 8 th gestational day of the intrauterine life, the embryonic vasculogenesis starts due to shear stress enhanced endothelial function, creating the first blood vessels followed by the appearance of the first fetal heartbeat by the 21 st day (Meyers, 2007).
Furthermore, disturbed flow dynamics in the prenatal period, could induce congenital anomalies (Al-Ghazali, et al., 1989). Some symbolic examples of cardiac malformations are resumed on (Table 5) of cardiac malformations on (Table 4).
Modified flow Conotruncal defects: TGA, TOF, DORV, DOLV, (Rothenberg, 2003). In the postnatal period, endothelial dysfunction is a major predisposing factor to hemodynamic troubles, circulatory disorders such as diabetes (Kapur A, De Palma R., 2007), arterial hypertension (Martini, et al., 2006), atherosclerosis (Chatzizisis, et al., 2007) and lifethreatening conditions (e.g. cardiogenic shock, multiple organ failure). This could be induced by disturbed flow dynamics due to pump failure and/or elevated vascular resistances. As a symbolic example, right ventricular (RV) failure can occur either due to elevated pulmonary vascular resistances caused by pulmonary oligemia, pulmonary hyperemia; or due to RV pump failure caused by ischemia, congenital anomalies, arrhythmia, valvulopathy, and/or accessory circulatory driving forces failure like with failed Fontan's operation (Pereira & Shirali, 2005).

Types of endothelial dysfunction
Practically, and in a matter to facilitate the therapeutic approach for cardiovascular pathologies, endothelial dysfunctions could be classified into three categories as follows ):  Type A: endothelial dysfunction manifested with heart failure.  Type B: includes endothelial dysfunction patients with endothelial dysfunction with normal heart function (e.g. diabetic, systemic arterial hypertension, PAH, erectile dysfunction, etc).  Type C: represented by healthy individuals, liable for endothelial dysfunction pathogenesis under certain circumstances like disturbed atmospheric pressure and gravity (e.g. Astronauts, professional scuba divers, bedridden); fatigue, increased inflammatory responses, increased apopotosis (e.g. athletics, early aging processes).

Endothelial dysfunction vs. current CVD therapies
Usually, endothelial dysfunction occurs as a consequence of pathological and/or interventional cardiovascular conditions, unfortunately with bad prognosis as there is no real curative option. A symbolic example, as been schematized in (Figure 3), regarding the current management of ischemic heart disease (IHD), which is still the leading cause of death so far. Except cracking or bypassing atheroma nothing has been done effectively until present.
As been resumed in (Figure 3): there are three symbolic "R" therapeutic options of myocardial ischemia which means: Reperfusion through an interventional and/or surgical approach; Rehabilitation, with physical exercise or CAD; Replacement with cellular therapy www.intechopen.com (WU KH, et al., 2006) or heart transplants. Also there are three conflictual therapeutic factors "F": F1 due to patients clinical varieties like with unstable angina; silent ischemia; STelevated myocardial infarction (STEMI) or non-ST elevated myocardial infarction (NSTEMI); mechanical complications of IHD; cardiogenic shock (Berger PB, et al., 1999); age or sex. This is complicated by anatomical variation; variations in myocardial damage that affects the septum, right or left ventricular regions (Haji SA & Movahed, 2000); and variable coronary pathology, including normal, spasmodic, vasculitis, (Newburger, et al., 2004), or classical coronary atherosclerosis. Second factor (F2) is related to therapeutic defects like with nitrates tolerance (Abrams J, 1988); finally the most important factor (F3) is the maintained endothelial dysfunction (e.g. atheroma).
Unfortunately, all those therapeutic options could not resolve the problem, means to restore the main cause of dysfunctional endothelial atherosclerotic plaques (Davignon , et al., 2004).
In addition, there are several varieties of MI due to other endothelial dysfunction pathogenesis rather than atherosclerosis such as coronary spasm (Kusama, et al., 2011) or congenital anomalies (McCrindle, et al. 2007), that could not be managed easily with angioplasty or coronary grafts (Gershlick & Thomas, 2007).
Otherwise, restorations of the endothelial function could be provided by the present concept (3R-in-one).
In general, the present arts of cardiac assists devices can be classified in two categories: 1. Devices that increase coronary blood flow during diastole, in order to improve the oxygenation and thus the performance of the myocardium. This category includes the intra-aortic balloon pump (IABP), (Burkhoff , et al., 2006) and the enhanced external counterpulsation pump (EECP), (Bonetti, et al. 2003). These devices must be synchronized with heartbeat and unsuitable in case of cardiac arrhythmia; and 2. Devices that unload and bypass the heart pump: either partially as achieved by left ventricular assist devices (LVAD), right ventricular assist devices (RVAD), and by extracorporeal membrane oxygenation (ECMO); or completely like with biventricular assist devices, extracorporeal circulation (CBP), hetertopic heart transplant. It should be emphasized that ECMO partially deviates some of the venous blood to an external membrane oxygenator. ECMO does not completely unload the right ventricle (RV) and that may explain its successful applications in pediatrics patients who are more frequently vulnerable to RV failure (Wilmot, et al. 2011). As a matter of fact, development of CAD remains controversial due to the induced momentum energy losses with the tasks of increased morbidity and mortality.
Most probably, CAD may aggravate hemodynamics, leading to multiple organ failure and death due to several factors that could be directly linked to devices themselves or indirectly due to patients' related factors as follows: 1. Devices related factors: a. Concept and design: a CAD is typically a lumped model constructed according to laws of physics for driving a Newtonian compressible fluid inside a closed pressurized hydraulic circuits (Roselli RJ & Brophy, 2003), implementing rigid tubes with fixed diameter. Meanwhile in practices a CAD is confronted with a non-Newtonian fluid (blood, running in flexible vessels with different geometries). This confrontation between two opposite pressurized hydraulic circuits ( Figure 4) creates a vicious circle of momentum energy losses manifested clinically by increased vascular resistances with endothelial dysfunction (e.g. hemorrhage, thromboembolism, inflammatory response, apoptosis, etc.), up till multiple organ failure. b. Driving forces' drawbacks: more precisely, roller or centrifugal pumps are usually used to circulate and perfuse blood between the patient and the external circuit most commonly in a steady flow mode of perfusion (Gravlee, 2008). Unfortunately even with biocompatible, materials the effect of sucking and pumping a fragile fluid like blood mechanically with impellers, propellers, or pulsed reservoir, inside narrow rigid conduits create a zone of turbulence and vortices with important energy losses (Geankoplis, 2005). This improper simulation of a ventricular function with current CAD, as it is practically impossible to replace a type III passive pump like the heart, by type II, or I pump (Anderson,1999). c. Installations systems: usually conduits of tubes, and cannula, made of biocompatible materials (e.g. PVC®, Dacron®, PTFE®, etc.), are used for connection between patient and CAD. In addition, those conduits need to be securely stitched to cardiovascular tissues, diverted under the skin (tunnelization) to allow proper chest closure, then to be de-aired and checked for leakage or gas emboli before finally connected to their corresponding CAD. Furthermore, the distance between a CAD and the patient' inlet/outlet sites gives rise to dead space, creating an additional momentum energy losses zone(please refer to Figure 8). Finally, the procedures for installing such conduits need to be carried out by experienced surgeons in specialized centers on patients who are fragile, and who have usually already been operated on several times in the past, increasing the risks of morbidity and mortality (e.g. hemorrhages, vascular complications, infections, multiple organ failure). The aggravating factors inherent to the patients themselves can be of several kinds such as: a. Age, sex: most CAD devices are unsuitable for patients with small body surface area (e.g. children, female) since more than 80% of CAD devices are designed for body areas of more than 1.5 m 2 , i.e. corresponding to adult heart patients. In addition CAD are generally first designed for management adult heart diseases and then miniaturized to cope with pediatric populations. However; pediatric patients are more vulnerable to hemodynamic disturbances caused by right heart failure due to congenital anomalies and they are vulnerable to vascular complications caused by small vessels geometries in content (Potapov, et al 2007). Adults usually suffer from ischemic left ventricular heart diseases with atherosclerotic vessels and they are therefore more vulnerable to vascular complications . b. Etiology: fate of CHF patients with severe right ventricular (RV) failure (CVP>16mmHg) is worse, compared with those patients with left heart sided pathologies. Current therapies employing CAD to treat CHF patients with severe RV failure (Prutkin et al. 2008), still exhibit a high mortality rate (65%-95%), most probably due to insufficient understanding of the great difference between the right and left heart circuits (Sollano, 1998). c. Preclinical studies: in particular, the role of animal models in therapeutic evaluation, which is an extremely essential procedure before proceeding to clinical applications of new CAD. However, there is still a gape between the chosen animal model and clinical realities as presented in the following examples: i. Current models of myocardial infarction are unfortunately, driven by costs rather than clinical resemblance. For example, rat as a most popular selected model is far from human physiopathology with a heart rate> 400 bpm. ii. Models of acute pulmonary hypertension (PAH), as often done either by hypoxia, monocrotaline, or systemic-pulmonary shunt. However, a lack of robust models of PAH, is still missing due to different spectra of lung tissue between species and humans (Robbins, 2004), (Bauer, et al. 2007). iii. The biventricular heart failure models, often called for testing of cardiac assist devices, which remain difficult to achieve in animals. The most part of these mechanical assists devices are usually tested in computational version (Querzoli, 2011) or WindKessel models, away from the pathophysiological aspect in humans (Olufsen & Nadim A, 2004

Proposal
The present concept proposes clinical applications of these tangential forces of shear stress in order to regulate the endothelial function so as to improve the hemodynamic of patients, the overall microcirculation of vital organs, and, when it has failed, to reestablish normal operation of the cardiac pump in a manner that is as physiological as possible, without replacing any organs and without any traumatic intrusion, to provide a method that is as minimally invasive as possible.
Development of a CAD* with an optimum function, which means improving hemodynamics, increasing organ microcirculation, restoring and preserving deficient endothelial function in a diseased human being, should compromise the following steps: maintaining the circulatory flow dynamics in the patient's systemic and pulmonary circulations; and temporarily relieving the heart of its pumping function.
* CAD is referred to a "circulatory assist device", instead of the commonly applied term "cardiac assist device".
More precisely there are three manners to stimulate the endothelium with a mechanical assist device as follows ( Figure 5): 1. Direct internal endothelial stimulation that will be induced by an intravascular catheter device. 2. Indirect internal endothelial stimulations with a pulsatile perfusion flow generated by a pulsatile pipe (tube) device at the left heart side. 3. External stimulation (pulsatile suit) at the right heart side endothelial with gentle rhythmic squeezing of the venous and lymphatic capacitances reservoirs at the superficial veins and capillaries.
www.intechopen.com According to the present concept, the method consists in using at least one device external to the patient's body and connected by at least a pipe and/or a specific connection element to: 1. Increase the preload of the right ventricle so as to improve myocardial oxygenation and so as to improve its contractility; and/or 2. Unload the left ventricle and diffuse regular pulsatile flow in the proximity of the aortic root so as to improve the hemodynamics of the left ventricle of the heart; and/or 3. Stimulate the endothelium mechanically by shear stress enhancement so as to release several mediators of endothelial vasodilators like nitric oxide (NO), to reduce the systemic and pulmonary vascular resistances (afterload).

Synchronization with the diastolic phase
The synchronization of these new pulsatile CAD with the heartbeat is strictly guided by the therapeutic indications according to types of endothelial dysfunction as follows ):  Type A: this means in case of heart failure, CAD's synchronization is unnecessary and must be unsynchronized with heartbeat.  Type B: synchronization of CAD with the heart is necessary to restore the endothelial function.  Type C: synchronization of CAD is relative, because according to the Starling's law (Katz, 2002), the cardiac output (CO) adapts to the venous return (RV preload).

Devices
In known manner, the prior art constituted in particular by circulatory assistance systems such as LVAD, RVAD, Biventricular AD, etc., simulate the ventricular pump by complex driving forces.
In a manner that is very different, and indeed that is opposite in the physical sense of the word, the devices and methods of the present concept are designed to maintain circulation in columns of blood within their own physiological containers as constituted by veins and arteries. The idea is to maintain a pulsatile blood stream complying with the biophysical and physiological standards of pulmonary and systemic circulations, by applying mechanical endothelial stimuli of shear stress.
One aspect of the devices and methods of the present concept enables shear stress endothelial stimuli to be increased, thereby enabling a microcirculation opening to be created in various organs of human body by means not only of conventional mediators of vasodilators such as nitric oxide, but also by means of other new vasodilators processing.

Pulsatile suit
In one aspect of the present method, blood is compressed from the outside of the body by means of a special suit referred to as a 'pulsatile suit", of the kind described in patents applications (WO/2008/000111) and (WO 2010/070018), which suit is used primarily to provide circulatory assistance to the right heart and secondarily as a device that makes it possible to obtain an overall hemodynamic improvement. The pulsatile suit is composed of three layers and must be suitable for the postoperative situations and provided with security features as following: 1. Inner layer made of elastic material (e.g. neoprene) to insure smooth tight massage like pulsed surge at the skin. 2. Middle sandwiched layer filled with gelatinous fluid, to alleviate the vigorous inflation/deflation, power induced by the driving force. 3. External layer made from tougher materials to keep the pulsed wave inwards toward the body. This part is equipped by security air releasing valve to prevent over inflation accident in case of mechanic defect. 4. Holes are previewed in the suit body, in order to facilitate medical administrations and prevent bedsores. 5. Layers thickness and design are modified according to age, body weight and indication of the patient. 6. The back portion of the trunk part of the suit (vest and belt) must not be inflatable in order to avoid any spinal, or back injuries. 7. Blood must be pulsed back from periphery towards the heart in a sloping progressive wave in longitudinal axis. Except at the chest part, pulsations must be started backward -forward towards the front, in a horizontal axis in such a manner to increase venous return within respect of the respiratory movement.
Naturally, this pulsatile suit has detachable parts and may take on various forms such as a hood, a pair of trousers, a jacket, a glove, a boot, or a sock. The parts could be reassembled together in one unit and wrapped tightly around the patient body through straps and zippers, as shown in ( Figure 6) and as patents descriptions.
Figures 12 show such suit covering the bottom portion of the human body, which the therapist (doctor, nurse, or even the patient) can put into place without effort. The suit may be connected directly to an external pump, it may be actuated by the therapist himself or herself.
The structure serves advantageously to guide the pulsations it generates, progressively in the venous return direction. It thus constitutes a circulatory assistance device for the right ventricle (RVAD).

Pulsatile tube
In another of its aspects shown in (Figure 7), the method implements at least one specific "pulsatile pipe" that serves to impart pulses to columns of blood, and that is preferably used in the context of providing circulatory assistance to the left ventricle (LVAD). Such a pipe is described in particular in patents applications (WO/2008/000110) and (WO 2010/066899). It may form part of a pulsatile medical kit that also includes a conventional pump (with or without oxygenator) placed at one end of the pipe, and an aortic cannula is placed by surgeon as close as possible to the patient's aorta. It is preferably prefilled in its intermediate space with an inert fluid such as helium, CO 2 , etc. This diminishes the risk of embolism since the gas initially present in the pipe is discharged outside the circulation. In addition, the pressure forces required for operating the pulsatile device are reduced. It can readily be understood that this device is invasive to a very small extent. It generates pulsations in most effective manner and it is very easy to implement. It may be put into place surgically via a mini-incision or via a percutaneous approach and then synchronized with the patient's electrocardiogram. Practically, circulatory perfusing systems create a state of momentum energy losses that could be identified in 6 main zones (Z0-Z5) , as follows ( Figure 8): (Z0) it represents the pre-oxygenator zone, where momentum energy losses depend on types of driving forces (e.g. (e.g. roller or centrifugal pump) to be deleted as well as the oxygenator, which is a major constant site of energy losses; (Z1) it is the zone downstream to the oxygenator, where energy losses depend on circuit conduit types (length, width, materials) and fluid viscosity; (Z2) it is represented by the pulsatile tube wedged at the arterial perfusion line between the oxygenator and aortic cannula; (Z3) it represents the pre-aortic cannula zone, which is the first effective pulsatile zone; (Z4) it represents the aortic cannula zone, where the effect of convergent (at the entrance) and divergent (at the tip) energy losses plays an important role (Cutlera D 1999); (Z5) it represents the perfused tissues started from the tip of the aortic cannula, causing important divergent momentum energy losses. At (Z3) where the effective pulsatile flow starts, theoretically this pre-aortic cannula zone represents a convergent diffuser with low momentum energy losses at the entrance of the aortic cannula. Meanwhile, a short (Z3)'s distance is requested to reduce turbulence and vortices that might occur due to strong-pulsed flow within a fixed geometries' tube. Furthermore, the pulsatile tube serves to reduce the empty space between monitor system and the tube itself, thereby giving rise to optimized operation with minimum pulsatile pressure; it is thus possible to envisage miniaturizing the device and correspondingly reducing the energy needed for its operation.
As seen in (Figure 12) a pulsatile pipe may be placed between the left subclavian artery and the right subclavian vein.

Pulsatile catheter
Another aspect of the present method comprises a "pulsatile catheter" comprising a conventional catheter that is surrounded by an inflatable element over a portion of its length (Figure 9). Such a catheter is disclosed in patent applications (US/2011/021987) and (WO 2009/136035). According to (Figure 9), the invention relates to a device for creating a pulsating inflation of an inflatable component (11) of a catheter (8), comprising: a bag (1) that can be filled with fluid (2); a bag compression means (5) capable of compressing said bag (1) in a pulsed manner; and a connection means (3) connecting said bag (1) to said inflatable component (11) of the catheter (8) and allowing the fluid (2) to move between said inflatable component (11) and said bag (1).
Advantageously, the inflatable element in place around the catheter presents in the deflated state an outside diameter that is less than that of the remainder of the catheter. Naturally, the inflatable element is connected to external inflation means suitable for generating pulsations during inflation. The device advantageously makes it possible to avoid excessively enlarging of the point where the catheter is inserted into a blood vessel.
Such a device is used in particular for PAH with increase in the afterload of the right ventricle (right ventricular failure); the catheter is placed in the trunk of the pulmonary artery by a percutaneous venous approach, preferably in association with a pulsatile suit.

Pulsatile console
An example of the pulsatile console ( Figure 10), is described in patent application (US 2011166515) that console is very simple in design and easy to use. The console enables determined pulsatile pressure to be created and applied to a pipe, a catheter, or ay other equivalent means. A simple source of fluid under pressure such as a bottle of an inert fluid, or of liquid under high pressure constitutes the continuous source that is transformed into a pulsatile source by the pulsatile console as disclosed therein. www.intechopen.com The invention relates to equipment for applying a determined pulsatile pressure to a medical device, comprising: a withdrawing means (2) designed to withdraw fluid from a source of fluid in continuous flow at high pressure; a conversion means (3) designed to convert said fluid into a fluid in a pulsatile flow at low pressure; at least one application means (105) for applying said fluid, as a low-pressure pulsatile flow, to said medical device; and a means (104) for removing said fluid.

Smartcan
According to yet another aspect of the present method, a secure and almost non-invasive connection is provided between the patient and external mechanical systems for providing circulatory assistance ( Figure 11). This aspect may be achieved by a device of the kind described in patent application (WO 2011/089162).

Fig. 11. The Smartcan conduit device
That device entitled the "Samartcan", makes it possible advantageously to group together all of the tools that make it possible to obtain a cardiovascular approach that is effective, fast, safe, and inexpensive. Thus, the tool enables a single operator, makes it possible to avoid all of the traditional steps such as incision, suture stitches, purse strings, etc. That simplifies the operation. Operating costs are thus significantly reduced.
Such a tool may be put into place and moved with assistance and remote guidance, e.g. echocardiography. This avoids blind guidance under the patient's skin for connecting the patient with an external circulatory assistance machine as with prior art methods. Such a connection gives rise to complications for the patient such as infections, hemorrhages, problems of closing the chest, etc.
In an advantageous manner, such a tool can be used as an aortic cannula, a cardiac cannula, a vascular catheter, or indeed as tubing for cavity drainage.
Such a tool, and more precisely the body of the device, is preferably prefilled with a liquid such as heparinized serum in order to reduce the risks of gaseous embolism and in order to shorten operating time.
In a novel and advantageous manner, the distance between such a tool and the patient is very small. In other words, the distance between a circulatory assistance machine (CAD) and the puncture sites (on the patient) is very short; in particular when implantation is performed close to the subclavian artery. This characteristic greatly reduces the energy losses that are inherent to existing devices.
The present invention relates to a single-use device to be used in surgery each time that a vascular approach by means of cannulation or catheterization is deemed indispensable (cardiopulmonary bypass, anesthesia, emergencies, resuscitation), particularly during cardiac surgery or interventional cardiology. Said novel device substantially includes a body (5), a sealing system consisting of two inflatable diskettes (4), a control connector for inflating and deflating the diskettes (4), a tubular unit (6) and a flexible guide (1). Upper right panel: shows a Smartcan with folded (G2) and unfolded (H2) external diskettes. Lower right panel: shows the Smartcan manually controlled guide wire before (E) and after penetrating a blood vessel (F). Left panel global schema of the Smartcan (A) and the proximal end (B) with the intraortic obstructive dikette (2), the cardioplegia delivery holes (3).

l'Orthèse cardiaque
According to another US patent application in pending, the various devices (pulsatile pipe, suit, and catheter, in particular) implemented in the present disclosure are synchronized together or separately as a function of the patient's hemodynamic parameters.
It relates to a novel therapeutic technique and method of providing mechanical circulatory assistance using a CAD that is minimally invasive. The CAD improves hemodynamics and microcirculation, and restores the endothelial function when it is insufficiently stimulated, particularly for a patient suffering from congestive heart failure (CHF).
The device complies with the patient's hemodynamic parameters as a function of breathing frequency and cardiac rhythm. Heart rhythm is detected by the electrocardiogram or by pacemaker as a function of variation in arterial pressure and/or in systemic and pulmonary resistances.
Synchronizing the pulsatile suit, thereby increasing venous return (preload) and reducing afterload, needs to be performed without hindering the frequency of breathing and without increasing central venous pressure above 16 mmHg. The pulsatile frequency of the suit may be less than the cardiac frequency of the patient (one-third to two thirds of the heartbeat). In contrast, the pulsatile pipe associated with the patient's electrocardiogram may be synchronized with cardiac rhythm and the pulsatile catheter may be faster than heart rate.
In particular, the devices and methods of the present CAD avoids problem associated with blood circulation through two well-separated circuits (systemic and pulmonary) that are constituted by the vessels and arteries of the patient and by the mechanical circulatory assistance device (s).
All of those pulsatile means enable variations in blood pressure to be created in vessels in application of the physical laws that apply to non-Newtonian fluids. They allow stagnant blood to be moved in compliance with Bernoulli's law, i.e. from the walls towards the insides of the vessels. This therefore gives minimizes the traumatic effects on erythrocytes.
When the heart pump, and in particular the left ventricle, is to be relieved (unload), the practitioner will use a Smartcan device in a version that enables an incision via the tip of the left ventricle or a left intra-atrial transeptal incision.
Similarly, when regular pulsations are to be produced and diffused close to the aortic root, the same device may be inserted as an arterial perfusion cannula in the root of the aorta or in the subclavian artery via a percutaneous approach or by echocardiographic guidance. Figure 12 shows a patient fitted with a pulsatile suit that covers the bottom portion of the body; in addition, a pulsatile jacket is placed around the patient's thorax and pulsatile sleeves are placed on each of the patient's upper limbs. In this embodiment of the invention a pulsatile pipe is placed between the subclavian artery and the subclavian vein.
Furthermore, the present CAD is suitable for managing various types of heart failure, regardless of the right or left etiology.
On the right heart, by putting pulsatile suit into place, the device makes it possible to reduce the stagnation of venous capacitances; by implementing a pulsatile catheter, it is possible to reduce the pulmonary afterload.
On the left heart putting a pulsatile pipe into place enables physiological pulse pressure to be maintained and directly serves to improve overall hemodynamics by reducing systemic vascular afterload.
Thus, the methods and devices according to the present disclosure may be defined as a circulatory orthosis, as opposed to prosthesis. Unlike orthotopic transplantation, the present disclosure makes it possible to keep the patient's heart in place, thus allowing the patient to wait in relative comfort for a histocompatible donor.
The present method provides bridging treatment prior to transplantation, thereby improving prognosis and morbidity by restoring patient's hemodynamics. As a reminder, present-day mortality is higher for right ventricular failure it lies in the range of 65% to 95%.
The present disclosure makes it possible to restore the endothelial function progressively by maintaining quasi-physiological shear forces on the endothelium; consequently, there is a significant improvement in the function of myocardium, thus making it possible avoid subsequent transplants.
The present disclosure provides and approach that is invasive to a very small extent, since it avoids risky surgical acts, in particular, the invention avoids sternotomy and/or thoracotomy which can be put off until subsequent transplantation.
The devices and method of the present disclosure thus makes it possible to cope with the shortage of donor and with the numerous problems that are associated with antirejection treatments.
In addition, the present CAD is adapted to all age categories, from newborns to patients of great age and/or patients that are most clinically fragile.

Experiments
These devices were evaluated in vitro, as well as with clinical volunteers. The in vivo study was approved by the Animal Research Facility at Sun Yat-Sen University and conformed to the Guide for the Care and Use of Laboratory Animals (NIH Publication No.85-23, Revised in 1996). In original pediatric animal models of acute cardiogenic shock state, created in piglets. We have avoided any premedication or any prophylactic medical support that may interfere with the endothelial function (e.g. atropine, -blockers, etc.). Only mechanical cardiac support was provided with the evaluated device compared to traditional therapies in control groups. The clinical volunteers were medical doctors included the author.

Evaluation of the pulsatile tube device
Perfusions of the circulatory system with devices like the cardiopulmonary bypass (CPB) and CAD disturb endothelial shear stress (ESS), which is responsible for the postcardiotomy syndrome, increasing liabilities of clot formation, bleeding, disseminated syndrome, etc (Bick et al., 1976)) (Abshire, 2009). This endothelial dysfunction syndrome is most probably occurred due to steady flow, foreign surfaces and the severe momentum energy losses. To overcome these side effects different therapeutic strategies are currently applied (Nour S, 2003), such as: a) pharmacological supports using antifibrinolytic (Cooper, 2006), inotropes, vasodilators, platelets, etc. (Nardell, 2009), but with some side effects as well (Ishida, zt al., 2004); b) normothermia: that becomes more practiced in CPB with some proven advantages over hypothermia (Pouard, et al., 2006), which may be explained because blood is nearly Newtonian at 37.2°C (Box, et al. 2005). Meanwhile, the benefits of normothermia on myocardial protection and microcirculation improvements remain controversial (Rastan, et al., 2008), as the myocardium is already protected with doses of cardioplegia, while the perfusion of microcirculation is more or less helped by the Fahraeus-Lindqvist effect due to hemodilution; c) total or partial absenteeism of CPB: that becomes popular with proven postoperative hemodynamic advantages, but it is still a challenging technique reserved for selected groups of patients (Shroyer, et al., 2009); d) pulsatile perfusion flow devices: in a matter to keep ESS some pulsatile CPB have proven advantages clinically and experimentally (Ündar, et al.,1999); (Undar, et al. 2006). Despite that, recent studies recommend the unphysiological steady flow (Voss, et al., 2010). This may be explained by pulsatile CPB inadequate curves with the necessity of a double perfusion pumps system to compensate the oxygenators momentum energy losses. Instead associating an intra-aortic balloon pump (IABP) with a conventional CPB, as a cost-effective manner (Onorati, et al., 2007), creates turbulent zones of vortices (Geankoplis, 2005), with vascular complications (Sanfelippo, et al.,1987) and controversial effectiveness ( Kadoi Y & Saito, 2000).
Alternatively, the pulsatile tube represents a potential solution for those aforementioned CPB and CAD drawbacks The pulsatile tube device (Figure 7), was evaluated as a potential solution for these CPB and CAD drawbacks. A device prototype was tested in vitro (a mock circuit) for energy losses studies and in vivo as a LVAD, also the tube prototype was associated in the in vivo study of a Bi-ventricular assist device (l'orthèse).

In vitro study
Materials and methods: a double lumen tube prototype as shown in (Figure 13), composed of: a) external polyvinyl chloride (PVC) (20 cm length, ½ inch diameter). b) Internal Polytetrafluoroethylene (PTFE) (18 cm length, 12mm diameter), reinforced with latex membrane (condom), as a protector against the PTFE micropore. c) 2 connectors (¼ inch) introduced at each end of inner tube and wedged to the PVC tube and securely sealed by external adhesive straps and rings. A small animal ventilator (HX-300 TaiMeng Technologies Inc ® ), was applied as a pulsatile generator.

Methods
With variant pump flow rate (400, 600, 800 and1000 ml/min) and fixed pulsation rate (110 bpm), we have compared circuit momentum energy losses during steady and pulsatile flows in 3 different tube positions as following:  Energy losses I: the tube was positioned downstream to the oxygenator at 6 cm from the aortic cannula (Figure 15-I).

Statistics
Continuous variables are expressed as the meanSEM. Comparisons between groups of independent samples were performed with student t-test hemodynamic data. P with a value less than 0.05 was considered statistically significant. GraphPad Prism® software was applied for all the statistical analyses in this study.

Results
As been resumed in (Table 5) and ( Figures: 16 & 17), momentum energy losses were significantly increased with the pulsatile tube in positions: III and II, compared to position I. Furthermore, there were observations of an increased perfusion pressure at P5 from the initial P1 of those groups (II and III), signifying severe turbulence at the post-cannula zone, which theoretically, corresponds to patient's aorta. There were minimum momentum energy losses with the steady flow in position. I, In contrast to positions II and III, there were important vortices with obstructive zones that created a sort of retrograde flow even before pulsations.

Comments
In this study, a steady perfusion flow was transformed successfully into pulsatile flow with a simple double lumen tube integrated into the arterial perfusion line of a conventional CPB circuit. According to our previous explanations (Figures 4 and 8), quantification of circulatory perfusion devices (CPB, CAD) depends on their momentum energy losses. The Bernoulli's principles of energy losses could be applied with accuracy in vitro to quantify lumped models like CPB (Undar et al., 2007). In vivo vessels elasticity and vascular tone bring CPB quantification more closer to Newton's law of shear stress as a major stimulant for endothelial NOS / resistances control.
The resulted energy losses have proven the importance of the pre-cannula zone represented in position I by P4, compared to P3 and P2 with positions II and III respectively showing severe turbulent flow with important vortices constitutions at this zone or (Z 3). Finally, the prototype by its position downstream to oxygenator could avoid an important obstructive zone of energy losses, which is almost constant with current CPB necessitating a double perfusion pump system and special low resistance oxygenator.
Conclusion CPB induces momentum energy losses with severe endothelial dysfunction. Current pulsatile devices induce inadequate curves with high costs. Pulsatile tube, adaptable to a conventional driving system could induce homogenous, downstream and nearly physiologic pulsatile perfusion flow with low momentum energy losses. This is a cost-effective method, promising low mortality and morbidity, especially in fragile cardiac patients.

In vivo study (study in progress)
The pulsatile tube device was tested as a left ventricular assist device (LVAD), in pediatric animal models (piglets) with acute myocardial ischemia.
Materials and methods: in the pulsatile group: a prototype of a pulsatile tube was realized in the same manner as the in vitro study, then a short piece of 14 Fr. PVC tube was modified as a aortic cannula (Figure 19), in a matter to avoid the conastant energy losses caused by current cannulae length with narrow tips. Same a small LV vent was attached to the other end of the tube. The whole system was connected to a pulsatile generator console (HX-300 TaiMeng Technologies Inc ® ). In the control group: a centrifugal pump (Sorin group Revolution ®), was connected to a standard aortic cannula (12 Fr. DLP®-Medtronic, Inc.) and apical vent (14 Fr. DLP®-Medtronic, Inc.).

5
Time 2 (T2) = after 1 hr of ischemia without any medical support 6 LVAD System switched on for 1hr.

9
Time 4 (T4) data collection before animal sacrifice Table 6. Summary of the surgical steps Operative schema and steps of surgical protocol are resumed in ( Figure 20) and (Table 6) respectively.

Results
This ongoing study results showed better hemodynamic with lower cardiac enzymes in the pulsatile group compared to control ( Figure 21) and (Table 7). (2) (3) (1) (4) Fig. 22. Pulsatile tube perfusion curve in vivo, as a LVAD in acute MI piglet The pulsatile tube's perfusion curve was nearly physiologic with complete discharge of the LV and unsynchronized with heartbeatt, as have been demonstrated on the operative movies.

Comments
The exposed results proved the feasibility as well as the effectiveness of the pulsatile tube as a LVAD. These preliminary results have shown hemodynamic improvement and myocardial recoveries, lower cardiac enzymes in the pulsatile group, compared to control. This hemodynamic improvement was significant in the pulsatile tube group and despite the maintained coronary obstruction in a fragile pediatric model, with very poor coronary collaterals. Interestingly we've tested the tube alone without a perfsuion pump and LV vent, as an endocardial stimulator. Myocardial recovery and macroscopic disappearance of the ischemic zone were obvious after few minutes (< 5min), of unsynchronized pulsations (please refer the attached movie). This was ended by severe vasodilatation and cardiac arrest. Currently, we are trying to overcome these drawbacks, particularly, the inner tube (PTFE) microporosity and vasodilatations, with a new generation of pulsatile tube prototypes.

Evaluation of the pulsatile catheter device (in vivo)
Prototype: a standard IABP catheter (8 Fr., 30 cc) was modified. Briefly, its original balloon membrane was peeled off and replaced with a small piece of commercial rubber balloon, secured and tied manually at each end of the catheter. This created an inflatable compartment of 11 cm. The distal part of the prototype was connected to a cardiorespiratory monitor (BIOPAC® physiology monitoring system, ECG channel). For a pneumatic rhythmic driving force, it was attached to a small animal ventilator (HX-300 TaiMeng Technologies Inc ® ). It was tested for leakage while pulsating in a heparinized saline bath. Once the prototype was inserted into the pulmonary trunk, the circuit inflation volume was adjusted (usually between 50-90 ml) to avoid right ventricular outflow tract obstruction. The ventilator was pulsed at a frequency of 110 cycles/min. The prototype device was tested in two animal model studies for acute MI and acute PAH as follows:

Acute myocardial ischemia model
(part of the results was presented at the 17 th conference of ACTVS,  Material and methods: Twelve piglets (8.3 ± 1.5 kg) were given either pulsatile (P: n=6) or nonpulsatile (NP: n=6) nitrates treatment. Both groups underwent permanent left anterior descending coronary artery (LAD) ligation with a median sternotomy ( Figure 23). After 1 h of ischemia, heparin was injected (150 IU/kg). In group P, a prototype CAD, driven by a small ventilator, was introduced into the pulmonary trunk and pulsated intermittently over 1 h at 110 bpm, irrespective of heart rate (73 ± 16 bpm). In group NP, nitrates were given (7±2 g/kg/min) for 1 h. Animals survived ischemia for 2 h in group P vs. 93±30 min in group NP.
With the macroscopic disappearance of infarction (Figure 24), group P exhibited improved hemodynamics ( Figure 25) and significantly lower myocardial apoptosis (0.66±0.07) compared to group NP (4.18±0.27), (Figure 26). Vascular resistances (dyne.sec/cm -5 .kg -1 ) were significantly lower (P<0.01) in group P vs. group NP: pulmonary resistance was 119±13 vs. 400±42, and systemic resistance was 319±43 vs. 1857±326, respectively. Myocardial endothelial NO synthase mRNA expression (Figure 27), was higher in group P (0.90±0.09) than in group NP (0.25±0.04; P<0.01), probably due to endogenous pulmonary NO secretion. after 1H of shunt and T3= end of 1h therapy. at T1 (baseline) and the end (T3). PVRI (dynes.sec.cm -5 /kg) were significantly lower (p<0.01) were significantly lower at T3 in group P compared to group NP. Left panel showing the cardiac output (CO) from both groups P and NP. CO (L/min) was with significantly improved at T3 in group P compared to group NP (p<0.01), in group P (red color) compared to group NP (bleu color). Representative figures from both groups showing apoptotic cells manifestations (red arrows), from both groups: group P (left) and group NP (right). The apoptotic index (AI) in group P was significantly lower than that in group NP (P<0.01).

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RT-PCR results shown with statistics, in which myocardial eNOS expression was significantly higher in group P (left) compared to group NP (right). (p<00.01).

Fig. 27. Myocardial eNOS mRNA expression
Left panels: samples from the non-pulsatile, nitrate treatment group (NP); right panel: sample from the pulsatile treatment group (P). Notice the relatively well-preserved myocardial microstructure in group P. Bar scale on each graph equals one micrometer.

Comment
Decalogue of original observations emanated from the present preliminary study as follows: i. Hemodynamic improvement, with significant recovery of the myocardial contractility and cardiac output (CO), despite maintained coronary obstruction. This was obvious macroscopically, and confirmed by low myocardial apoptosis manifestation, and relatively well-preserved cardiomyocytes organelles in the pulsatile group P. ii. Intrapulmonary shear stress enhancement, that was induced successfully and for the first time according to literatures, as that was practiced with uncertain results, using an intra-aortic balloon pump (IABP) (Letsou et al. 1993). The uncertainty is probably due to differences between vessel geometries and catheters diameters, in addition the right heart side has specific morphological particularities that must be considered (Burton, 1954), (Huang W & Yen RT, 1998). iii. Endogenous vs. exogenous nitric monoxide (NO): generally, NO has an important effects on the cardiovascular system as a potent vasodilator, inhibitor of platelets aggregation and myocardial contarctility (Jones SP & Bolli, 2006). Shear stress induces endogenous NO production by activating endogenous nitric oxide synthase (eNOS). (Chatzizisis et al., 2007), like during physical exercise Walsh et al., 2003). Also exogenously administered NO donors like Nitrates, can to be deleted induce eNOS (Ignarro, et al.,2002). Therefore, the study results showed that physiologically induced NO was superior to exogenous nitrates in acute IHD syndrome. iv. Microcirculation vs. collaterals, in group P, the increased expression of myocardial eNOS mRNA (Depre, et al. 1997); with fewer apoptotic cells (Mital, et al., 2002) could be explained by endogenous NO due to the intrapulmonary catheter pulsation. Meanwhile the exact mechanisms of action remain to be explored. However several conditions supported the role of microcirculation, as the subendocardial resistance vessels are more sensitive to mediators of vasodilatation and endothelium dependent dilators (Pelc, 1987). In consideration of the short biological lifetime of NO (Doherty et al., 1998), and the maintained coronary ligation, the chosen model is known for poor coronary collaterals, in addition to the immature myocardium in young pig model (Gorge, et al. 1989). This may be explained by an undiscovered endothelial mediator(s) that improved myocardial microcirculation in the group P. in group P. v. Reperfusion injury syndrome to be deleted, interestingly the study results showed that immediate myocardial reperfusion might be unnecessary. The procedure, provides stabilization as well as myocardial and hemodynamic recoveries without the urgent need of reperfusion with the well known consequences of the reperfusion injury syndrome (Heinzel, et al., 2008). This was confirmed with our ongoing study, using an intrapulmonary catheter device induced percutaneously through the jugular vein. vi. Right heart vs. left heart endothelium, this study suggested that the right heart endothelium responded rapidly, to shear stress stimuli, compared to the left heart endothelium, which is most frequently, stimulated with devices like IABP and EECP, known for tolerance and long with long term effectiveness respectively (Pagonas, 2010). We found that the PA endothelium was hypersensitive; a few minutes of intrapulmonary pulsations were more than sufficient continuous intrapulmonary catheter pulsation (2 animals were expired). We then shifted from continuous to intermittent pulsation controlled by hemodynamic readings (5-10min pulsation) interrupted by pause intervals (10-15 min). vii. Venous vs. arterial approach, the systemic arterial approach is most commonly practiced in IHD management, typically with IABP and/or PCI procedures. However, these require specific operative environments with high risks of risk vascular complications (Busch, et al. 1997); (Dangas, et al., 2001). Instead, the study provides a safer and cost-effective venous approach for IHD management that could be done by an ER therapist without the need to specific cardiac centers facilities. viii. Diastolic CAD synchronizations vs. unsynchronized pulsatile catheter, contrarily to present synchronized cardiac assist devices (CAD), like the IABP, EECP, etc., we believe that unsynchronized catheter pulsation simplifies and broadens its application as an efficient cost-effective method for IHD management. Recorded pressure curves showed that the delivered catheter pulsation was faster than the heart rate; Nevertheless, it did not disturb right ventricular hemodynamic or obstruct the outflow tract. ix. Suitable for almost all kinds of myocardial ischemia, as been observed, hemodynamic stabilization could be achieved after a few minutes of device pulsation without any pharmacological supports. Positioned inside the PA trunk, the device can reduce pulmonary afterload without jeopardizing preload in case of RV ischemia. Its small dimensions allow applications in pediatrics and other cases of non-atherosclerotic IHD (e.g. congenital, spasm, or vasculitis, induced MI. Moreover, in preconditioned (Bolli R, 2001), hibernating, stunned myocardial or permanent ischemic lesions (Vroom MB & van Wezel, 1996), long term intermittent intrapulmonary or intracoronary sinus catheter pulsation could restore myocardial tissues and dysfunctional endothelial coronary lesions. x. The pulsatile catheter device vs. CAD, compared to current CAD drawbacks, an autonomous small catheter driven by a portable or implantable pacemaker-like generator, could be safely inserted into the circulatory system of any patient or chosen vessel, including arterial, venous or umbilical. And most probably, it could restore atherosclerotic endothelial lesions and endothelial dysfunction with the pulsatile catheter insertion into the intrapulmonary or intracoronary sinus in coronary atherosclerosis or into the main lumen of a diseased systemic artery (e.g. carotid, renal, femoral, etc.). An enhanced external counter pulsation studies in animal models have shown that regular application of endothelial shear stress stimuli could improve conditions related to atherosclerotic endothelial dysfunction (Zhang, et al., 2007). This could be a supportive argument for the concept.
In summary, An intrapulmonary pulsatile catheter device could improve hemodynamics and recover acute myocardial ischemia efficiently, compared to nitrates. This could be induced with an appropriate intrapulmonary catheter device, adaptable to vessel geometries, regardless of coronary occlusion and irrespective of the heartbeat. The procedure represents an innovative and cost-effective method for IHD management, particularly through an intravenous percutaneous approach (ongoing study).
www.intechopen.com "Flow and Rate": Concept and Clinical Applications of a New Hemodynamic Theory 55 9. Acute pulmonary arterial hypertension* Pulmonary arterial hypertension (PAH) is a dysfunctional endothelium disease with increased pulmonary vascular resistances (PVR) and poor prognosis. Current therapies are still insufficient. Alternatively, we propose a the pulsatile catheter device as a more effective for PAH management compared to traditional treatments.
Material and Methods: Twelve piglets (10.3 ± 3.8 kg) were given either intrapulmonary pulsatile (P: n=6) or non-pulsatile (NP: n=6) Tadalafil treatment. After median sternotomy and heparin injection (250 IU/kg), both groups underwent aorto-pulmonary surgical shunt during 1 h then removed (Figures 29 and 30). Over a second 1 h period: in group P, a catheter prototype, driven by a small ventilator, was introduced into the pulmonary trunk and pulsated intermittently at 110 bpm, irrespective of heart rate (90.6±10.74 bmp). In group NP, Tadalafil were given orally (1 mg/kg).
Assembled shunt showing: 2 PVC limbs unequally cut with ½ cm; connected together with silicone tube and equipped with 2 stopcocks and pressure lines connectors, prefilled with heparinized saline and clamped ready before insertion. Aorto-pulmonary shunt in place with infundibular intrapulmonary artery pressure line (white color). Fig. 30. Aortico-pulmonary "U" shape external shunt system.
Statstics: Continuous variables are expressed as the meanSEM. Comparisons between groups of independent samples were performed with student t-test for eNOS and a 2-way ANOVA for hemodynamic data. P with a value less than 0.05 was considered statistically significant. GraphPad Prism® software was applied for all the statistical analyses in this study.
Results: hemodynamic and cardiac output (CO) were significantly (p<0.05) better in group P compared to group NP: CO was 0.56±0.0.26 vs. 0.54±0.11 (L/min) respectively. Mean pulmonary artery pressure (PAP) was significantly dropped in group P compared to group NP: PAP was 9.6±2.97 vs. 32.25.07 respectively. Vascular resistances (dynes.sec/cm -5 .kg -1 ) were significantly lower in group P vs. group NP: pulmonary resistance (Figure 31) Comment This study confirms the dominancy of the right heart over the left heart and hemodynamic through PVR The effect of intrapulmonary shear stress enhancement was immediate upon both PVR and SVR in the group P. The significant improvement of hemodynamic with rapid reduction of pulmonary pressure in group P compared to the group NP, confirms the dominancy of shear stress-mediated endothelial function enhancement method over traditional therapies*.
Also this confirmed what we have mentioned with the ischemic models regarding the hypersensitivity of the right heart side endothelium of the pulmonary artery compared to systemic arteries.
Conclusions: Induced with an appropriate device, intrapulmonary shear stress-mediated endothelial function enhancement, provides a more effective nearly physiological therapy for PAH.
* Abstract of the study concept was presented at the 16th conference of ACTVS -Singapore, . Paper in press, submitted to the Pediatric Cardiology Journal (Nour, S 2012). Operative movies: http://www.nourmd.com.

Evaluation of the pulsatile suit device
This concerns the non-invasive devices (pulsatile suit) that were tested in vivo and healthy volunteers (the author and medical doctors colleagues).

Animal model of acute RV failure*
Cardiac assists devices (CAD) for right ventricular (RV) failure remain controversial with poor results. The purpose of this study was to evaluate a pulsatile suit CAD in an acute RV failure model vs. current therapies.
Material and methods ( Figure 32): twelve piglets, divided in two equal groups: pulsatile group P and non-pulsatile group NP. Acute pulmonary incompetence was created surgically through median sternotomy. Management started once severe RV failure observed (48.1±24.5 min): in group P, a pulsatile trouser, driven by pneumatic generator was pulsated intermittently at 40 bpm, irrespective of heart rate (104±27 bmp). Group NP, was treated with oral Tadalafil (1 mg/kg), IV fluids and adrenaline (0.3g/kg). Operative movies: http://www.nourmd.com.

Mask
Pulsatile mask was tested in healthy volunteers (n=8) from both sex (age:19-68 ys), subjected to 20 minutes of low pressure (0.2-0.6 bars) pulsatile mask, synchronized with diastolic heart rate. Statistics: Continuous variables are expressed as the meanSEM. Comparisons between groups of independent samples were performed with student t-test hemodynamic data. P with a value less than 0.05 was considered statistically significant. GraphPad Prism® software was applied for all the statistical analyses in this study.
Results: hemodynamics and cerebral blood flow was significantly improved (p<0.05), as manifested by Doppler flow measured at the common carotid artery ( Figure 35) (Figure 34), was rapidly increased after 15 min of pulsations, then dropped slightly to pass in plateau over the second 15 min of stimulation. This proves the physiological effect of the device that does not stun endothelial biology, allowing self-cellular regularization in response to induced endothelial vasodilators mediators and unlikely to exogenous NO donors vasodilators (e.g. nitrates).

Trouser
Pulsatile trouser, that covering almost the trunk, was tested in healthy adult volunteers (the author and medical colleagues) (n:6), were subjected to a low pressure (1.2 bars) fixed pulsations (60 bpm) and without synchronization of heartbeat (72± 17 bpm). Results ( Figure  36)

In vivo
The device was tested in an acute ischemic biventricular failure (piglet). This was created by mid ligation of the LAD, and elecrocauterization of the RV coronary artery branches, for details refer to the attached operative movies site. The preliminary results shown better hemodynamic responses with the biventricular assist device combing the pulsatile tube as a LVAD and the pulsatile trouser as RVAD (Figure 36). Comment: in this study the device (l'Orthèse cardiaque) was tested as well in total cardiac arrest followed and acute ischemic biventricular failure and cardiogneic shock. The device was successfully capable to circulate the stagnant blood columns within the respect of the biophysical conditions of each heart circuit biophysiological conditions (please refer to the attached movie). The study pending new pulsatile tube constructions. The object is to maintain circulatory flow dynamics and cellular metabolism in case of acute biventricular failure until improvement of hemodynamic or arrangement for heart transplants with compatible donors in nearly physiological condition.

In clinical volunteer
The pulsatile trouser was indicated in a CHF patient, (a medical consultant from the UK), as an ultimate therapeutic option, according to a consensual patient's request. The patient was short-listed for both heart and kidney transplant, then been removed due to severely deteriorated hemodynamics: EF ≈ 15%, systolic pulmonary arterial pressure >65 mmHg, and elevated BNP (1100 pg/ml). He was on renal dialysis (6 days/ week), chronic constipations and oxygen sleep dependent. The pulsatile trouser was applied for 2O minutes daily, in a posture position* with fixed frequency (40 bpm), irrespective of patient's pacemaker (78 bpm) and low inflation / deflation pressure (1.4 bar). The patient recovred regular bowl, and became less dependent on oxygen during the first week of treatment. After two months there was hemodynamic improvement: EF≈ 20%; systolic PAP ≈ 41mmHg and BNP ≈ 500 pg/ml. The patient reintegrated the NHS transplant program. Despite, hemodynamic improvement, the procedure was interrupted because a cholecystectomy was urgently, needed for biliary lithiasis, which may promote to shower pancreatitis with the trouser pulsations. *N.B. In CHF patients, it is preferred to apply trouser therapy in a posture position, rather than supine position to amplify the gravity effect as an enhancement factor of shear stress with more voluminous columns of venous capacitance.

Comment
These aforementioned preliminary results have proven the feasibility of the concept as a promising therapeutic approach for CVD. On other word, proven the efficiency of the right heart endothelial reservoir as a physiological therapeutic backup compared to optimum traditional therapies in addressing acute cardiogenic shock state.
The pulmonary endothelium, stimulated with a small size pulsatile catheter that can be introduced intravenously and percutaneously, open a new era in cardiology as almost all types of ischemic heart disease as well as pulmonary arterial hypertension (PAH). Macroscopic disappearance of the ischemic zone confirmed with low myocardial apoptosis and that despite permanent ligation of the coronary artery means improved hemodynamic is more related to open myocardial microcirculation in neonate animal model known with poor coronary collaterals. A significant drop in the pulmonary vascular resistance was the key of hemodynamic improvement. This can be induced with the proposed pulsatile systems after short period of intermittent shear stress-mediated endothelial function stimulations at the splanchnic and hepatic venous capacitance, or at the pulmonary artery, and irrespective to heart rate.
Pulsatile suit concept results that have been obtained in volunteers also open a new era of therapeutic approach in nearly all types of endothelial dysfunctions pathogenesis as follows: with (Type A), endothelial dysfunction with heart disease patients; in Type B, with endothelial dysfunction and normal heart function (e.g. diabetic, systemic arterial hypertension, PAH, erectile dysfunction, etc); and Type C, as prophylactic in healthy individuals, liable for endothelial dysfunction pathogenesis (Astronauts, bedridden, etc) as well as a circulatory hemodynamic physiological stimulus (e.g. athletics, anti-aging, etc).
The pulsatile mask can improve the cerebral circulation directly through the cavernous venous systems, and systematically through the jugular vein system, current studies show enhancement of the retinal artery flow as well as diameter, which ca be effective in treating early neurodegenerative diseases and stroke patients. This improvement is observed at points remote from the pulsating zone, i.e. where the suit was being worn.
A clear improvement in microcirculation has also been observed at the fingertips as a result of putting a pulsatile suit (trouser) on the bottom portion of a patient's body as shown in (Figure 36).
Practically, delivery of shear stress stimuli at the compliant pulmonary artery (PA) zone (zone5), can be induced according to the Bernoulli's principles with a small size pulsatile catheter adaptable to the pulmonary trunk geometries for shear rates enhancement at the inner boundaries layers, irrespective of heartbeat without obstructing the right ventricular outflow tract. Meanwhile at the superficial venous capacitance (zone1) shear stress enhancement could be achieved externally with the pulsatile suit.
At the left heart side, an endothelial shear stress will be induced by the pulsatile tube. The pulsatile tube could adapt whether a conventional CPB or CAD, provides a nearly physiological pulse pressure with lowest momentum energy losses, particularly in association with the Smartcan. It will considerably reduce the distance between CAD and the perfused artery (Z3).
Similarly, an improvement in the microcirculation of the myocardium has been observed in an ischemic model by permanent ligation of the left anterior descending coronary artery (LAD), after applying shear forces generated by pulsatile catheter inserted in the pulmonary artery forming part of the right circuit of the heart.
Given the very short lifetime of nitric oxide, it cannot reach zone that are remote from the site where it is secreted, since it is necessarily absorbed by hemoglobin before reaching said remote zones. Thus, it has been found that at least one mediator mechanism other than those that are already known and secreted by the endothelium is capable of triggering the opening of microcirculation. The devices and methods of the present concept advantageously enable such secretion to take place.
As a priority, assistance should be provided to the right portion of the heart. It is known that the right heart "dominates" the left heart and controls hemodynamics by pulmonary resistances . Isolated ventricular assistance, on the left or right, can then be envisaged in accordance with the present disclosure; and after that assistance for the left heart.
The method makes it possible to restore the endothelial function progressively by maintaining quasi-physiological shear forces on the endothelium; consequently, there is a significant improvement in the function of myocardium, thus making it possible avoid subsequent transplants.
Alternatively, the pulsatile catheter prototype, when applied in the clinic, could be implanted into the pulmonary artery through a central venous line (ongoing study), in hospital settings, it could be connected to a small portable-implantable driving device. Patients with catheter device set implants would benefit from real-time hemodynamic measurements and simultaneous therapeutic pulmonary pulsation. Thus, this approach promises to be cost-effective.
By providing immediate improvement of myocardial microcirculation, the device could become a first priority in IHD as well as PAH managements.
In future investigations, the device could be inserted through the PA (ongoing study ) or coronary sinus, either associated or not with an absorbable stent, to test for enhancements in the restoration of endothelial function.
Over the long term, shear stress-induced endothelial regulation, alone or in combination with progenitors and angiogenic factors could promote cardio-circulatory rehabilitation and accelerate cardiogenesis. This approach might eliminate the need for interventional or surgical procedures.
Finally, as far as the concept has been proven therapeutic efficiencies, there were some study limits that should be resolved in the future. This includes the severe vasodilatation as a result of direct intravascular endothelial stimulations by the intrapulmonary pulsatile catheter as well as the pulsatile tube as a LVAD.
Interestingly, the application of the pulsatile tube alone as a LVAD without perfusion pump induced severe vasodilatation after impressive improvement of MI (please refer to operative movie). This is proving the hypersensitivity of the pulmonary endothelium as well as the LV endocardium that were responded rapidly to the unsynchronized tube pulsations.
Meanwhile, vasodilatation that could be induced by exogenous NO donors, leads to hypovolemic-cardiogenic shock. In contrast, the observed study hypovolemia, was preceded by general improvement of hemodynamic and organ microcirculation. This was manifested by the increased renal output manifested by a vesical globe that was released spontaneously in the pulsatile group animal models, which could be easily compensated by IV fluids. Currently we reduced the frequencies of pulsatile time (5-10 min), interrupted by interval pause guided by hemodynamic monitors, particularly systemic BP.
There was no observed severe vasodilatation with the externally stimulated endothelial devices (the pulsatile trouser and mask). By caution, as the mechanism of vasodilatation is still undiscovered, also the improved microcirculation became almost steady after 15-20 min of external endothelial stimulations, our recommendation for the pulsatile suit sessions is: 20-30 min. Furthermore, it is unnecessary to apply high-pressure pulsatile volume. A low pressure (1.2-2 bars) is sufficient to stimulate the superficial intravascular blood volume, covered by their endothelial stocks.
Contraindications of the pulsatile suit, are more or less relatives as a non-invasive device, meanwhile cautions may be considered with some patients (e.g. hepatic cirrhosis, malignancy, open fractures, 3 rd degree burns, colostomy, cerebral accidents, malignancy). Under all circumstances, Clinicians will determine contraindications according to the obtained results.
Currently, clinical programs of the non-invasive devices will start very soon, with (Type A, & C) endothelial dysfunction patients (e.g. CHF, resistant arterial hypertension, cerebral atherosclerosis, etc.) and others with healthy persons (Type C) e.g. bedridden, athletes.

Conclusion
A promising therapeutic approach for CVD and circulatory disorders management with more physiological cost effective manners compared to current therapies. According to physics, it consists of: a shear rate intravascular enhancement device (catheter); a steady flow transformer device (tube) and an accessory circulatory driving forces enhancement and/or replacement device (suit). Drawbacks of the invasive devices could be overruled through accurate mathematical calculations of the induced momentum according to individual body surface area and the stimulated sites (blood column). Means, optimum devices performances could be achieved with computational models and biomedical engineering, to define the accurate device geometries as well as materials.