Aortic Arch Baroreceptor Implants for the Treatment of Hypertension.

Abstract

An implant device and related treatment method for hypertension are provided herein. Such an implant device is configured to be placed in a target region of a patient's aortic arch, thereby sufficiently stretching the arterial wall in the target region to induce a baroreflex. Typically, the implant is designed to stretch the target region in the aortic arch by at least 20%, while still allowing the arterial wall to be exposed to pulsatile flow and allowing lateral blood flow to secondary branch arteries. The implant includes two or more expandable structures interconnected in series by axially expandable flexible connectors, and can adapt to the curvature and complex geometry of the aortic arch to secure the implant in the aortic arch while favorably stretching the target region. The target region includes a cylindrical segment of the aortic arch between the left common carotid artery and the left subclavian artery.

Description

[Technical field]

[0001]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 336,818, filed April 29, 2022, and U.S. Provisional Application No. 63 / 443,656, filed February 6, 2023, the disclosures of which are incorporated by reference in their entireties herein.

[0002]

[0002] In one aspect, the present invention relates to implantable devices, and related components, systems and methods, for the treatment of hypertension. [Background technology]

[0003]

[0003] Hypertension affects one in two adults in the United States. However, only 24% of patients have their blood pressure adequately controlled. Hypertension is the leading preventable cause of heart attacks, strokes and death. However, a 10 mmHg reduction in blood pressure reduces this cardiovascular risk by 20%.

[0004]

[0004] Despite documented poor medical compliance of patients to antihypertensive drug regimens, pharmacotherapy has been the mainstay of hypertension treatment for decades. In 2004, a landmark trial of a catheter-based medical device (i.e., Symplicity1) first demonstrated the blood pressure lowering effect of renal denervation with a radiofrequency ablation catheter. Findings from additional clinical trials of renal denervation with radiofrequency and ultrasonic energy (i.e., the SPYRAL and RADIANCE trials, respectively) confirmed these findings, but with more modest blood pressure lowering results of around 5-10 mmHg in ambulatory recorded systolic blood pressure.

[0005]

[0005] An intravascular implant developed by Vascular Dynamics for hypertension relies on a stent-like device that is inserted into the carotid artery and lowers blood pressure by stretching the arterial wall from the inside and enhancing the carotid baroreflex. In a 2017 study, this carotid baroreflex modulation device significantly reduced ambulatory recorded systolic blood pressure, more than double that reported in a renal denervation trial. Clinical results initially appeared promising, with several patients reporting dramatic blood pressure reductions that lasted for 2-3 years, but clinical results were mixed as some patients suffered transient ischemic attacks (TIAs), preventing further testing and subsequent development.

[0006]

[0006] Another challenge arose with regard to deploying the device in the carotid sinus, which is the primary target of the device. Because the carotid sinus carries blood to the brain, any difficulties encountered in this area, such as trauma to the arterial tissue during deployment, subsequent device dislodgement and / or plaque buildup in the area due to the device or trauma, may contribute to a TIA or stroke, resulting in adverse or fatal patient outcomes. For clinicians lacking experience with this sensitive area, performing procedures in this area, such as placing a carotid stent, may pose unnecessary risks to the patient.

[0007]

[0007] Thus, there remains a need for devices and methods for treating hypertension that provide the clinical benefits seen in the baroreflex response, but avoid the considerable drawbacks associated with the conventional approaches described above. There is a further need for devices that allow for improved ease and consistency of implantation to avoid the adverse effects described, that allow for implantation for a wide variety of clinicians, and that more reliably provide good patient outcomes for reducing hypertension over the long term. Summary of the Invention

[0008]

[0008] The present invention relates to an implantable hypertension treatment device for deployment within the aortic arch and related treatment methods.

[0009] In one aspect, the present invention relates to a method for treating hypertension in a patient. Such a method can include deploying an implant in the patient's aortic arch, the implant including a plurality of expandable structures, each of the plurality of expandable structures having an expanded configuration and a collapsed configuration. In the collapsed configuration, the implant is advanceable through the vasculature, and in the expanded configuration, the implant engages the arterial wall of the aortic arch. The method further involves stretching at least a portion of the arterial wall along a target region of a cylindrical segment that wraps around the aortic arch (particularly along the inner curvature) by engagement of one of the expandable structures, thereby eliciting a baroreflex response of baroreceptors in the target region, and exposing a majority of the arterial wall along the target region to pulsatile blood flow through one or more large openings in the implant so as to sustain the baroreflex response induced by the implant for an extended period of time. In some embodiments, the portion of the arterial wall is preferably stretched by at least 20%. In some embodiments, the target region is the entire cylindrical strip of the aorta between the left common carotid artery and the left subclavian artery. Preferably, the implant extends in both directions beyond the target area to ensure optimal engagement with the target region.

[0010] In another aspect, the present invention relates to an implant device for treating hypertension in a patient. Such an implant can include two or more expandable structures interconnected in series by a flexible connector, the expandable structures having a collapsed configuration for advancement through the patient's vasculature and an expanded configuration for engagement of an arterial wall in the patient's aorta. In some embodiments, each of the expandable structures is formed from one or more wires formed in an expandable design (e.g., one or more Nitinol wires formed in a serpentine, sinusoidal, or zigzag design to form a circumferential ring or band). In some embodiments, each expandable structure is defined by a single continuous wire. In some embodiments, each expandable structure is a laser cut design in a single tube. In some embodiments, the entire implant with multiple expandable structures and flexible connectors can be defined by a laser cut design in a single tube. In such wire or laser cut embodiments, the expandable structures can have a substantially circular cross section. In some embodiments, each of the expandable structures includes a plurality of elongated frames, each frame having a pair of struts defining opposing sides and spaced to define a large opening therebetween, and the frames are interconnected along adjacent sides to form a regular polygon cross-section.

[0011] In some embodiments, the implant includes three expandable structures, the middle expandable structure is disposed at the target location to activate baroreceptor nerves, and the proximal and distal expandable structures act as anchors to anchor the middle structure at the target location. In such embodiments, the expandable structures may be of the same or different dimensions. In some embodiments, the implant includes three expandable structures, the middle structure has a lateral dimension that is larger (e.g., 1.3 to 1.5 times) than the lateral dimensions of the proximal and distal expandable structures. This approach allows for more stretch (e.g., 30% or more) along the target area, as the proximal and distal structures aid in the transition of the arterial wall and inhibit tearing or dissection of the stretched vasculature. At least one of the expandable structures is dimensioned such that, when expanded within a target region of the aortic arch, a pair of struts on each frame stretches the arterial tissue in the target region sufficiently to elicit a baroreflex response of baroreceptors in the target region, e.g., 20% or more, while the large openings between the struts expose the arterial wall in the target region to pulsatile blood flow to sustain the baroreflex response for an extended period of time. It is recognized that the expandable structure can be any of those described herein (e.g., bonded frames, continuous wires, laser cut). [Brief description of the drawings]

[0012] [Figure 1A] 1A-1D illustrate an exemplary implant device deployed along a target region of a patient's aortic arch, according to some embodiments. [Figure 1B] 1 illustrates another exemplary implant device deployed along a target region of a patient's aortic arch, according to some embodiments. [Diagram 2] FIG. 1 shows a conventional diagram of the anatomical structure of the vasculature and baroreceptors targeted by conventional devices and the location of the carotid baroreceptors. [Figure 3A] FIG. 1 shows details of an exemplary type of baroreceptor called PEIZO1. [Figure 3B]FIG. 1 illustrates central nervous system responses to baroreflex stimulation in regulating blood pressure. [Figure 4] FIG. 1 illustrates the anatomy of the aortic arch vasculature. [Diagram 5] FIG. 1 illustrates embryonic anatomy that later develops into the aortic arch. [Figure 6] FIG. 1 illustrates the anatomy of the aortic arch showing additional details regarding the target region, in accordance with an aspect of the present invention. [Figure 7] FIG. 1 shows the histology of arterial tissue in the target area. [Figure 8A] FIG. 13 shows fluorescent staining images from an animal study showing the distribution of baroreceptors in target areas. [Figure 8B] FIG. 13 shows a fluorescent staining image showing the location of baroreceptors within the arterial wall of the aortic lumen. [Figure 9A] FIG. 1 shows results from a previous animal study showing higher sensitivity of baroreceptors in the aorta compared with those in the carotid artery. [Figure 9B] FIG. 1 shows results from a previous animal study showing higher sensitivity of baroreceptors in the aorta compared with those in the carotid artery. [Figure 10A] FIG. 1 illustrates an exemplary implant having two expandable structures interconnected by a flexible connector, according to some embodiments, where the structures are defined by four frames and have a square cross-section. [Figure 10B] FIG. 1 illustrates an exemplary implant having two expandable structures interconnected by a flexible connector, according to some embodiments, where the structures are defined by four frames and have a square cross-section. [Figure 10C] FIG. 1 illustrates an exemplary implant having two expandable structures interconnected by a flexible connector, according to some embodiments, where the structures are defined by four frames and have a square cross-section. [Figure 10D]FIG. 1 illustrates an exemplary implant having two expandable structures interconnected by a flexible connector, according to some embodiments, where the structures are defined by four frames and have a square cross-section. [Figure 10E] FIG. 1 illustrates an exemplary implant having three expandable structures, according to some embodiments. [Figure 11A] FIG. 13 illustrates an alternative embodiment of an implant, where the expandable structure is defined by three frames and has a triangular cross-section. [Figure 11B] FIG. 13 illustrates an alternative embodiment of an implant, where the expandable structure is defined by three frames and has a triangular cross-section. [Figure 12A] FIG. 13 illustrates an alternative embodiment of an implant, where the expandable structure is defined by five frames and has a pentagonal cross-section. [Figure 12B] FIG. 13 illustrates an alternative embodiment of an implant, where the expandable structure is defined by five frames and has a pentagonal cross-section. [Figure 13A] 13A-13D illustrate alternative embodiments of an implant having three expandable structures, with the intermediate structure having an increased lateral dimension, according to some embodiments. [Figure 13B] 13A-13D illustrate alternative embodiments of an implant having three expandable structures, with the intermediate structure having an increased lateral dimension, according to some embodiments. [Figure 13C] 13A-13D illustrate alternative embodiments of an implant having three expandable structures, with the intermediate structure having an increased lateral dimension, according to some embodiments. [Figure 13D] 13A-13D illustrate alternative embodiments of an implant having three expandable structures, with the intermediate structure having an increased lateral dimension, according to some embodiments. [Figure 14A]FIG. 14 illustrates various dimensions (A, B, C, D, E) and characteristics of the aorta that were examined in patient studies to determine the appropriate size of the implant construct for deployment within the aorta. [Figure 14B] FIG. 14 illustrates various dimensions (A, B, C, D, E) and characteristics of the aorta that were examined in patient studies to determine the appropriate size of the implant construct for deployment within the aorta. [Figure 14C] FIG. 14 illustrates various dimensions (A, B, C, D, E) and characteristics of the aorta that were examined in patient studies to determine the appropriate size of the implant construct for deployment within the aorta. [Figure 15A] FIG. 13 illustrates a mechanism of action in accordance with an embodiment of the present invention whereby an appropriately sized structure engages and stretches a substantially round (e.g., 25 mm diameter) aortic wall to achieve sufficient stretch to induce a baroreflex. [Figure 15B] FIG. 13 illustrates a mechanism of action in accordance with an embodiment of the present invention whereby an appropriately sized structure engages and stretches a substantially round (e.g., 25 mm diameter) aortic wall to achieve sufficient stretch to induce a baroreflex. [Figure 15C] FIG. 13 illustrates a mechanism of action in accordance with an embodiment of the present invention whereby an appropriately sized structure engages and stretches a substantially round (e.g., 25 mm diameter) aortic wall to achieve sufficient stretch to induce a baroreflex. [Figure 15D] FIG. 13 illustrates a mechanism of action in accordance with an embodiment of the present invention whereby an appropriately sized structure engages and stretches a substantially round (e.g., 25 mm diameter) aortic wall to achieve sufficient stretch to induce a baroreflex. [Figure 16] FIG. 1 illustrates a target region of the aorta, which is the entire aortic segment between the LCCA and the LSA, according to some embodiments. [Figure 17] FIG. 1 illustrates a delivery catheter configured to deliver and deploy an implant to the aortic arch, according to some embodiments. [Figure 18A] 1A-1D illustrate delivery of an exemplary implant to the aortic arch along a target region using a delivery catheter, according to some embodiments. [Figure 18B] 1A-1C illustrate delivery of an exemplary implant to the aortic arch along a target region using a delivery catheter, according to some embodiments. [Figure 18C] 1A-1C illustrate delivery of an exemplary implant to the aortic arch along a target region using a delivery catheter, according to some embodiments. [Figure 18D] 1A-1C illustrate delivery of an exemplary implant to the aortic arch along a target region using a delivery catheter, according to some embodiments. [Figure 19] 1 illustrates a method of treating hypertension with an implant, according to some embodiments. [Figure 20] 1 illustrates a method of treating hypertension with an implant, according to some embodiments. [Figure 21A-1] 13A-13D illustrate alternative designs of expandable structures for aortic arch baroreceptor implants, according to some embodiments. [Figure 21B-1] 13A-13D illustrate alternative designs of expandable structures for aortic arch baroreceptor implants, according to some embodiments. [Figure 21C-1] 13A-13D illustrate alternative designs of expandable structures for aortic arch baroreceptor implants, according to some embodiments. [Figure 21A-2] 13A-13D illustrate alternative designs of expandable structures for aortic arch baroreceptor implants, according to some embodiments. [Figure 21B-2] 13A-13D illustrate alternative designs of expandable structures for aortic arch baroreceptor implants, according to some embodiments. [Figure 21C-2] 13A-13D illustrate alternative designs of expandable structures for aortic arch baroreceptor implants, according to some embodiments. [Figure 21A-3] 13A-13D illustrate alternative designs of expandable structures for aortic arch baroreceptor implants, according to some embodiments. [Figure 21B-3]13A-13D illustrate alternative designs of expandable structures for aortic arch baroreceptor implants, according to some embodiments. [Figure 21C-3] 13A-13D illustrate alternative designs of expandable structures for aortic arch baroreceptor implants, according to some embodiments. [Figure 22] 1A-1C illustrate the relationship between compliance of a simulated aortic arch vessel before and after placement of an implant, according to some embodiments. [Figure 23A] 21A-1 through 21C-3 illustrate an exemplary implant utilizing multiple expandable structures interconnected by flexible connectors and deployed in the aortic arch, according to some embodiments. [Figure 23B] 21A-1 through 21C-3 illustrate an exemplary implant utilizing multiple expandable structures interconnected by flexible connectors and deployed in the aortic arch, according to some embodiments. [Figure 24A] 11A-11D illustrate alternative flexible connector designs between adjacent expandable structures for use in an aortic arch baroreceptor implant, according to some embodiments. [Figure 24B] 11A-11D illustrate alternative flexible connector designs between adjacent expandable structures for use in an aortic arch baroreceptor implant, according to some embodiments. [Figure 24C] 11A-11D illustrate alternative flexible connector designs between adjacent expandable structures for use in an aortic arch baroreceptor implant, according to some embodiments. [Figure 24D] 11A-11D illustrate alternative flexible connector designs between adjacent expandable structures for use in an aortic arch baroreceptor implant, according to some embodiments. [Figure 24E] 11A-11D illustrate alternative flexible connector designs between adjacent expandable structures for use in an aortic arch baroreceptor implant, according to some embodiments. [Figure 24F]11A-11D illustrate alternative flexible connector designs between adjacent expandable structures for use in an aortic arch baroreceptor implant, according to some embodiments. [Diagram 25] FIG. 1 illustrates another exemplary implant for treating hypertension configured to stretch an arterial wall both circumferentially and axially, according to some embodiments. [Figure 26] 26A-26D illustrate steps of deploying the implant of FIG. 25 in the aortic arch, according to some embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013]

[0040] In one aspect, the present invention relates to an implantable device for the treatment of hypertension configured for implantation in a target region within the aortic arch to induce a baroreflex response, thereby reducing blood pressure.

[0014]

[0041] I. Physiological baroreflex response To understand the physiological response of the baroreflex response, it is useful to understand the interactions between the nervous system within the patient's anatomy. Figures 2-3B show the location of baroreceptors with the vasculature, baroreceptor cells, and aspects of the baroreceptor's interaction with the central nervous system.

[0015]

[0042] Blood pressure sensation occurs at several hot spots within the vascular system. Afferents of the vagus nerve (i.e., cranial nerve 10) and glossopharyngeal nerve (i.e., cranial nerve 9) target the aortic arch and carotid sinus, respectively. Vagus sensory neurons access the aorta via a thin nerve branch called the aortic depressor nerve, and glossopharyngeal neurons access the carotid sinus via the carotid sinus branch (see Figure 2). The aortic depressor nerve and carotid sinus branch consist of co-fasciculating fibers that contain both mechanosensory and chemosensory afferents. Mechanosensory nerve fibers mediate the baroreflex. The ends of these mechanosensory nerve fibers have specialized nerve endings called baroreceptors that penetrate the arterial wall. Baroreceptors are stretch receptors and do not measure pressure directly, but rather sense arterial stretch. The blood pressure pulse that accompanies each heartbeat stretches the arterial wall radially, and this arterial distension in turn activates mechanosensitive neurons. Baroreceptor neurons are long aortic to brain sensory neurons that transmit input directly to the brainstem. Activation of these baroreceptor neurons decreases sympathetic output and increases parasympathetic output from the brainstem, ultimately decreasing blood pressure and heart rate (called the baroreflex).

[0016]

[0043] At the molecular level, baroreceptors are actually complex protein structures that form ion channels in the sensory endings of baroreceptor nerve fibers (see Figure 3A). Stimulation of the ion channels results in an influx of cations into the neuron and depolarization by signal transmission along the nerve cell. Baroreceptor nerve endings are located in the outer wall of the artery between the tunica media and tunica adventitia (see Figure 8B).

[0017]

[0044] Baroreceptor neurons are long arterial-to-brain sensory neurons that transmit input directly to the brainstem. Aortic arch baroreceptor nerve signals originate from the arterial wall, travel through the aortic depressor nerve, then via the superior laryngeal nerve to the vagus nerve, and thence to the brainstem (see Figures 2 and 3B). The brainstem reflexively modulates this signal, decreasing sympathetic output and increasing parasympathetic output to the circulation. Blood pressure and heart rate decrease. This cascade of events is called the baroreflex.

[0018]

[0045] Early animal studies demonstrated that this response is associated with stretching of the arterial wall, which occurs naturally in hypertension. Subsequent animal studies demonstrated that the baroreflex response can be either transient or sustained, depending on whether stimulation of arterial receptor sites is static or pulsatile, respectively. Static stimulation led to a drop in systemic blood pressure that normalized after a few minutes, whereas nonstatic pulsatile stimulation (e.g., similar to natural pulsatile blood flow) demonstrated a sustained drop in systemic blood pressure.

[0019]

[0046] Since the 1960s, modulation of the baroreflex, and in particular the carotid baroreflex, has been a primary target for device-based therapy in difficult to control hypertension. The first efforts involved pacemaker-type devices, i.e., electrodes placed around the carotid sinus nerve connected via wires to an implanted stimulator. Stimulation of this nerve, which innervates the carotid baroreceptors, can avoid stimulation within the artery and reduce blood pressure through the carotid baroreflex arch. This technology is continuing in human clinical trials. A similar type of device for the aortic arch baroreceptors, or more precisely the aortic depressor nerve, has been successfully used in a goat experimental model to reduce blood pressure. Still, pacemaker-type implants are unlikely to be a device-based solution for resistant hypertension due to their obvious drawbacks, namely, in part, because patients would prefer not to have a generator surgically inserted in their own chest. To overcome this limitation, Vascular Dynamics has developed a stent-like intravascular implant that stretches the carotid artery wall from the inside, amplifying the carotid baroreflex signal. The device has a non-articulating, monomorphic design configured for a straight segment of the proximal internal carotid artery. In early clinical trials, the device was successful in lowering blood pressure in a resistant hypertensive population, but with a small risk of transient ischemic attacks (TIAs). There are various drawbacks associated with this approach that may contribute to an increased risk of stroke and TIAs.

[0020]

[0047] The present invention seeks to avoid the above-mentioned shortcomings associated with conventional approaches by providing an intravascular implant that induces an improved baroreflex response in the aortic arch. In an exemplary embodiment, the present invention relates to an implant having one or more expandable structures configured to stretch the arterial wall along a target region of the aorta, particularly the aortic arch. In some embodiments, the present invention is configured to engage a target region of the aortic arch including the medial curvature opposite the left subclavian artery. This target region can be defined as the cylindrical segment of the aortic arch between the LCCA and the LSA. This portion of the aortic arch is particularly rich in baroreflex receptors, and these receptors are theorized to be more sensitive compared to baroreceptors in various other regions, such as the carotid sinus. Because this region of the aortic arch is believed to provide a high response, the implant may achieve a more consistent and reliable reduction in blood pressure. Additionally, implantation in this area avoids the shortcomings associated with delivery and implantation in sensitive areas of the carotid sinus, which may increase the risk of TIA and stroke. Thus, it is believed that the implants described herein provide a more robust baroreflex response to reduce blood pressure, improve ease of delivery and implantation, and reduce the risk of adverse events.

[0021]

[0048] Early animal studies of differential baroreceptor responses have identified anatomical "hot spots" of baroreceptors at various locations in the vasculature, including a narrow cylindrical strip extending circumferentially around the aortic arch between the origins of the left common carotid artery and the left subclavian artery (4th pharyngeal arch artery in Figure 4). This region is illustrated in the fluorescent staining image in Figure 8A, which shows baroreceptors stained red. This baroreceptor-rich area can be defined as the cylindrical segment of the aortic arch between the LCCA and LSA, shown as target T in Figure 4.

[0022]

[0049] These "hot spots" of baroreceptors originate from the embryonic pharyngeal arch arteries, as shown in Figure 5. The third pharyngeal arch artery develops into a symmetrical structure: the left and right carotid arteries. In contrast, the right fourth pharyngeal arch artery (R4PA) becomes the proximal right subclavian artery, while the left fourth pharyngeal arch artery (L4PA) develops into a relatively narrow cylindrical strip B of the aortic arch, as marked in Figure 6. This strip has distinct characteristics compared to other regions of the aortic arch.

[0023]

[0050] This strip of the aortic arch is histologically different from other areas, as it has fewer smooth muscle cells and an increased elastic lamina. Figure 7 shows in the left column a tissue section through aortic arch segment B, which shows fewer smooth muscle cells and an increased elastic lamina, compared to aortic section C in Figure 6, shown in the right column. It is in this region B that the more commonly known aortic arch baroreceptors are located (as shown in Figure 2). However, various animal and human studies have shown that there is indeed a unique regional distribution of baroreceptors in this region, extending along band B enveloping the aortic arch, as shown in Figure 8A. Additionally, baroreceptors in the aortic lumen are located in the outer layer of the arterial wall within the aorta, as shown in the fluorescent image in Figure 8B, which shows baroreceptor nerve fibers stained pink.

[0024]

[0051] There are very few human reports identifying the location of aortic arch baroreceptors. One early research study showed that baroreceptor nerves wrap around the aorta originating from the left subclavian artery, and the same authors later showed that they may extend around the aorta from the brachiocephalic artery to the ligamentum arteriosum. Several early studies have shown that baroreceptors are found along this region of the aortic arch extending to 40% of the circumference. Due in part to the tissue structure of this region described above, baroreceptors are thought to behave differently than baroreceptors in other regions, including the carotid artery. At least one animal study has demonstrated that the pressure threshold for stimulating an action potential is lower in aortic baroreceptors than in carotid baroreceptors (see Figure 9A). The animal study further suggested that uniaxial stretch of 20% induced a significant increase in cytoplasmic calcium fluorescence in aortic arch baroreceptor neurons, but not in carotid baroreceptor neurons, as shown in Figure 9B. Thus, aortic baroreceptors in the human aorta are thought to be more sensitive than those in the carotid artery. Thus, by utilizing an implant specifically configured for deployment in the aortic region to stretch the arterial wall in this target region, a more consistent and pronounced baroreflex response is possible than with conventional carotid implants.

[0025]

[0052] It is noted that the literature describes the presence of baroreceptors in various locations within the body, including the carotid arteries and aorta, and that several publications describing passive baroreflex implants mention in passing a list of various possible implantation sites, including the aorta generally, but do not teach any specific target region of the aortic arch. Moreover, none have addressed the unique challenges of implanting in the aortic arch region, challenges that have led prior approaches to focus primarily on the carotid arteries (which have typically been accessed to perform certain other procedures, such as placement of carotid stents to address stenosis in this region).

[0026]

[0053] Thus, the present invention seeks not only to provide an improved baroreflex response by implanting in a specific target region of the aortic arch, but also to improve ease of implantation while allowing for implantation at this unique site. Importantly, the claimed implant and approach avoids the drawbacks associated with procedure and implantation in this area that may undesirably lead to increased adverse events due to complications in deployment in the carotid artery.

[0027]

[0054] Although there are significant advantages to delivering an implant to the aortic arch, i.e., the ability to target aortic arch baroreceptors in the narrow band enveloping the aorta, there are also certain challenges associated with deployment in this area. Because the aortic arch is significantly larger in diameter than the carotid artery, the implant diameter must correspond to the diameter at the aortic arch to adequately engage the tissue to achieve the required stretch of the arterial wall (e.g., 20% or more, 20-50%, or even 20-100% stretch). Furthermore, to prevent inversion or rotation of the implant, the implant should preferably have a length substantially larger than its maximum lateral dimension (e.g., diameter), e.g., about 40 mm or more. In some embodiments, the overall implant length is 70 mm or more (e.g., about 85 cm).

[0028]

[0055] Another challenge is that the aorta is the main artery in the body, and therefore there is a large amount of blood flow that is carried through the aortic arch and into the secondary arteries (e.g., BA, LCC, LSA) that branch off from the aorta. Thus, to provide consistent engagement and stretching in the target area over time, the implant must be configured to withstand forces from pulsatile blood flow through the aortic arch, as well as lateral forces from blood flow directed into the secondary arteries, without dislodging. Furthermore, the implant should be configured to expose a large portion of the arterial wall in the target area to pulsatile blood flow to provide a sustained blood pressure drop as described above, rather than a temporary response if the arterial wall is isolated from blood flow. Yet another challenge is that the implant must allow free lateral blood flow to the secondary branch arteries. Thus, the implant itself is configured with large openings in the expandable structure that allow exposure of the arterial wall as well as allowing lateral blood flow to supply any adjacent secondary arteries.

[0029]

[0056] II. Exemplary Implant Devices 1A shows an exemplary implant device 100 for treating drug-resistant hypertension implanted within the aortic arch AA. The implant is an expandable device inserted into the aortic arch, which stretches the arterial wall of the aortic arch from the inside, lowering blood pressure by increasing the aortic arch baroreflex. Branching from the upper part of the AA are the secondary branch vessels, the brachiocephalic artery (BA), the left common carotid artery (LCCA), and the left subclavian artery (LSA).

[0030]

[0057] As shown, the implant 100 includes two expandable structures 10, 20 interconnected in series by an axially expandable connector 30. The expandable structures are positioned longitudinally along the aorta, which helps to secure and stabilize the placement of the implant within the curved aortic arch. Given the relatively large size, high blood flow rate, and curved morphology of the aorta, anchoring of a single expandable structure in this region may prove challenging. By utilizing two or more structures disposed along different portions of the aorta, the implant accommodates the curvature and complex geometry of the aorta to help anchor the implant in the target location. Additionally, by relying on the engagement of two or more structures along the aorta, the anchoring force of the implant is distributed over a larger area, thereby minimizing trauma to the arterial wall, which may reduce inflammation and thrombus formation that may contribute to the formation of atherosclerotic plaque. Although the first expandable structure 10 is shown deployed in an off-center deployed state, it is recognized that the structure may be centered over the target area T.

[0031]

[0058] FIG. 1B illustrates another exemplary implant device 110 for treating drug-resistant hypertension implanted within the aortic arch AA. This embodiment includes three expandable structures 10, 20, 40 interconnected in series by multiple flexible connectors 30. The implant is configured such that the middle expandable structure 40 is deployed in a target region T to activate baroreceptors in the region, while the proximal and distal structures 10, 20 act as anchors to provide additional stability and also help transition the arterial wall to the middle expandable structure. As illustrated, the middle expandable structure 40 can have a lateral dimension that is larger than the lateral dimensions of the proximal and distal expandable structures. Typically, the middle structure has a lateral dimension that is 1.2 to 2 times, preferably about 1.3 to 1.5 times, larger than the lateral dimensions of the proximal and distal structures. This configuration allows for more stretching of the arterial wall in the target region because the proximal and distal structures help stretch the arterial wall to a lesser extent, thereby transitioning the arterial wall to increased stretch in the target region. This reduces the risk of dissection along the target region from increased stretching because the proximal and distal structures distribute some of the force from the stretching in the central region. Additionally, this configuration provides greater stability of the middle structures in the target region. Various other aspects of this implant can be similar or the same as those described in FIG. 1A.

[0032]

[0059] As shown in FIGS. 1A-1B, the expandable structure can be formed by a plurality of open-ended wire frames formed by spaced apart struts defining each side. Adjacent frame sides are interconnected along side struts such that the frame forms a regular polygon that is axisymmetric along the longitudinal axis of the expandable structure. The expandable structure has a collapsed configuration for advancement through the vasculature (e.g., in a delivery catheter) and an expanded configuration (as shown) in which the side struts engage the arterial wall of the aorta, thereby sufficiently stretching the arterial wall between each pair of struts in the frame to induce a baroreflex response. The flexible connector 30 is axially expandable (e.g., a zigzag connector) allowing the two expandable structures to extend along different longitudinal axes to accommodate the various degrees of curvature and the complex three-dimensional geometry of the aortic arch. This configuration minimizes distortion of the aorta or adjacent great vessels and avoids compression injury to surrounding anatomical structures such as the left recurrent laryngeal nerve. Additional details regarding the expandable structures can be seen by reference to Figures 10A-12B. Although these embodiments depict implants defined by an interconnected frame, it will be appreciated that these aspects are applicable to a variety of other types of expandable structures, for example, expandable structures formed by one or more wires, or laser cut designs formed from tubes.

[0033]

[0060] 10A-10D show an exemplary implant device 100 having two laterally expandable structures 10, 20 interconnected in series by multiple flexible connectors 30. FIG. 10A shows a cross-sectional view and FIG. 10B shows a side view. FIG. 10C-10D show the same view, but the device is rotated 45 degrees along the longitudinal axis. The implant device may further include one or more visualization markers 31 thereon, such as, for example, a coating or a gold or platinum spot on the flexible connector 30, to aid in positioning during implantation. In this embodiment, the flexible connectors are axially expandable (e.g., zigzag connectors), and there are a total of four connectors extending between the vertices of adjacent crown portions of the first and second expandable structures. FIG. 10E shows an exemplary implant device 100'''' having three laterally expandable structures 10, 20, 40 interconnected by flexible connectors 30. It will be appreciated that some embodiments may further include additional such structures (eg, four, five, six, etc.) connected in the same or different ways.

[0034]

[0061] In this embodiment, each expandable structure 10, 20 includes four elongated frames (10a / 10b / 10c / 10d) joined along adjacent sides to form a square cross section, as shown in FIG. 10A. Each frame includes at least two straight strut sections 11, 12 that define opposing sides, and curved atraumatic crowns 13, 14 that connect the proximal and distal ends, respectively. The overall shape of the frame is therefore oval or pill-shaped. As shown, the atraumatic crowns 13, 14 are gently curved to form an arc of less than a semicircle, such that engagement of the proximal or distal ends against tissue does not cause trauma to the arterial wall. The struts and crowns define the overall frame, which leaves a large opening 15 through which the arterial wall is exposed to pulsatile blood flow, allowing lateral blood flow to secondary branch arteries. In some embodiments, the struts of adjacent frames are defined as single struts such that a square cross-section implant has only four struts total, one at each corner. It is further noted that the entire frame can be formed as a single continuous wire such that the crown and struts are different parts of the same wire. In some embodiments, the frame is designed to avoid any sharp corners or angled features less than 100 degrees, which ensures that the proximal and distal ends of the frame remain atraumatic and helps to avoid the formation of thrombus or plaque in the frame along the large openings where lateral blood flow is maintained. This design is advantageous because the square cross-section provides sufficient stretching of the arterial wall between the opposing side struts of each frame without overstretching any one portion of the arterial wall, yet still retaining normal function and blood flow of the aorta. While this embodiment includes two expandable structures interconnected by four flexible connectors, the implant can include additional expandable structures connected in series in the same manner, and can include more or fewer flexible connectors.

[0035]

[0062] It is understood that these concepts can be utilized in a variety of other shapes / designs, for example, triangular or any regular polygonal cross section as shown in Figures 11A-13D. Figures 11A-11B show an implant 100' having first and second expandable structures 10' / 20', each having a frame similar to Figure 10A, except that each component is formed by three frames such that the cross section is triangular (e.g., equilateral). In this embodiment, the maximum lateral dimension of the component is the length of each side of the triangle, stretching three portions of the arterial wall. Figures 12A-12B show yet another implant 100'' having first and second expandable structures 10'' / 20'', each having a frame similar to Figure 10A, except that each component is formed by five frames such that the cross section is triangular (e.g., equilateral). In this embodiment, the maximum lateral dimension is the distance between the apex and the midpoint of the opposing sides. 13A-13D show an implant 110 (see FIG. 1B) having three expandable structures 10, 20, 40, with the middle expandable structure 40 having a transverse dimension d2 that is greater than the transverse dimension d1 of the proximal and distal expandable structures 10, 20. The dimension d2 can be 1.2-2 times, preferably about 1.3-1.5 times, greater than d1. In this embodiment, the dimension d2 is 1.3 times greater than d1. As previously mentioned, this configuration further improves the stability of the implant device in the aortic arch and advantageously allows for further stretching of the target area than would otherwise be safely performed. This is accomplished by utilizing the proximal and distal expandable structures to transition the arterial wall, reducing the risk of dissection or tearing beyond the target area.

[0036]

[0063] In another aspect, the implant is specifically sized to the dimensions of the human aortic arch to engage the arterial wall with the side struts of the expandable structure to anchor the implant within the aortic arch and to fully stretch the arterial wall in the target area. In the embodiment shown in FIG. 1, the implant is positioned such that the first expandable structure 10 is positioned opposite the LSA along the target area of ​​the cylindrical band encasing the aorta, as previously described. Thus, engagement of the pair of side struts in this area stretches the arterial wall and stimulates the highly sensitive baroreceptors in this area. In some embodiments, the implant is sized to achieve a 2:1 implant to aortic diameter ratio at the baroreceptor target area.

[0037]

[0064] III. Sizing of Aortic Arch Implants The baroreceptor amplification device is an intravascular implant designed to amplify the baroreflex response by stimulation of sensitive baroreceptors at a precise location within the aorta. This is accomplished by appropriately sizing the implant as described herein to achieve sufficient stretching of the arterial wall in the target area (e.g., at least 15%, typically 20% or more). The implant is sized based on the unique morphology of the aortic arch in humans. In some embodiments, suitable applicable dimensions for such implants were determined by computed tomography angiography (CTA) studies of the human aorta. Aortic arch CTA measurements were obtained from 50 patients, including both men and women, aged 53 to 88 years. Measurements were tabulated and the average and range were determined according to Tables 1 and 2 below.

[0038]

[0065] Table 1 shows the averages of various aortic arch measurements, including the aortic arch diameter along regions A, B, C, D (see FIG. 14B) and the length E extending between sections A and D (see FIG. 14A). Table 1. Mean aortic arch measurements [Table 1]

[0039]

[0066] Table 2 shows the ranges of various aortic arch measurements, including the aortic arch diameter along regions A, B, C, D and length E as described above. Table 2. Range of aortic arch measurements [Table 2]

[0040]

[0067] In one embodiment, the diameter and length dimensions can be considered to exhibit relatively little variation as evidenced by the small standard deviation and narrow range. As shown in FIG. 14C, the aortic arch region has multiple distinct regions where a portion of the implant device can potentially be embedded or secured by one or more portions of the implantable device. Thus, the implant device design should not only accommodate the target region (e.g., typically region E), but can also include proximal and distal expandable structures configured to engage the inner diameter along the more proximal region (e.g., region F or G) and more distal region (e.g., regions A-D). Thus, it is believed that an implant can be made that is appropriately sized to fit most patients within the above ranges. Note that the arterial wall can be safely stretched up to 50% in healthy patients, and potentially up to 100%, such that variations in stretch due to differences in aortic dimensions can be tolerated as long as the target region is sufficiently stretched (e.g., at least 20%). In the alternative, these averages and ranges of dimensions can be considered to warrant different sized implants. In some embodiments, a set of different sized implants (e.g., 3-10 different sizes) can be provided, allowing easy selection of a size based on the specific measurements of a given patient's aortic arch (see Table 3 below). In another alternative, the implants can be custom made according to the patient's unique measurements. The latter two options may be well suited for patients with highly diverse morphologies or particularly complex geometries of the aortic arch.

[0041]

[0068] According to the above averages and ranges for the human aorta, two or more expandable structures can be suitably sized for placement within the aorta. In an exemplary embodiment, each of the expandable structures is 30-60 mm in length, typically about 40 mm in length, and has a maximum transverse dimension (e.g., diameter) of 30-55 mm, typically 30-46 mm. These dimensions accommodate most of the average adult aorta while at the same time providing the necessary stretch along the target area to elicit a baroreflex response. The expandable structures may be of the same or different lengths and may be of the same or different diameters.

[0042]

[0069] Table 3 below shows a set of different sizes and associated diameters of the implant based on a compilation of relevant dimensions of the aortic arch of over 50 patients from CTA studies. Component A refers to the more distal expandable structure (20 in FIG. 1) and Component B refers to the more proximal expandable structure (10 in FIG. 1) that is disposed in the target area. As mentioned above, the size of the implant can be selected to suit the unique morphology of the patient based on a CT scan of the patient's aortic arch. It is recognized that the set of sizes can include any of the sizes listed, or any combination thereof, as well as various additional combinations not listed. Table 3. Size (diameter) of implant configurations [Table 3]

[0043]

[0070] In another aspect, two or more expandable structures are connected in series by multiple flexible connectors. Preferably, the connectors are axially expandable (e.g., zigzag design) to optimize fit with the outer and inner curvatures of the aortic arch. In some embodiments, the connectors are axially expandable by 5-20 mm, typically about 5-10 mm. In some embodiments, the connectors are unexpanded 5 mm to up to about 10 mm, or more fully expanded, such that the connectors on the outer curvature of the aortic arch can be expanded while the connectors on the inner curvature of the aortic arch can remain unexpanded, as shown in Figures 1A-1B.

[0044]

[0071] In another embodiment, the length of each expandable structure is typically 30-50 mm, preferably about 40 mm, such that the total length of the entire implant, including the flexible connectors, is 65-110 mm, typically 70-90 mm, depending on the axial extension of the connectors. These lengths allow the implant to extend a minimum of 10 mm beyond both the lateral aspect of the brachiocephalic artery and the lateral aspect of the left subclavian artery to ensure a safe and stable loading zone for the device. Based on CTA studies, the implant is approximately 85 mm when the connectors are not expanded and approximately 10 mm or more (e.g., 10-20 mm) when the connectors are fully expanded.

[0045]

[0072] Based on previous animal studies, it is believed that human aortic arch baroreceptors need to be stretched a minimum of about 20% to achieve a significant increase in baroreceptor nerve signaling. As a result, the implant is dimensioned with a maximum transverse dimension or diameter that is a minimum of 20% greater than the natural diameter of the target area (e.g., measurement C from a CT angiography study). The diameter of the implant must be sufficient to ensure adequate apposition with the aortic arch wall at the terminal landing area just beyond the lateral origin of the brachiocephalic and left subclavian arteries (e.g., locations A and D in FIG. 13). For sizing purposes, the diameter of the implant is measured as the maximum transverse dimension (e.g., for a square cross section, the diagonal shown in FIG. 10A). Based on CTA studies, the implant can be sized to a variety of different diameters, e.g., 30, 34, 38, 42, 46, and 50 mm. The implant can be composed of components A and B of different diameters, e.g., as shown in Table 3.

[0046]

[0073] IV. Mechanism of Action To further understand implant sizing, one should understand the mechanism by which the implant reduces blood pressure. It is useful to consider the aortic arch as a circle in cross section and the arterial wall in individual arc lengths, as determined by the diagram shown in FIG. 15A and the arc length formula. In the case of an implant with a square cross section (as in FIG. 10A), the diameter of the aorta is considered to be a circle divided into equal parts (e.g., four equal parts). If the aortic arch diameter is 25 mm, the radius is 12.5 mm and each arc length is 19.6 mm, as shown in FIG. 15B. After inserting a 30 mm diameter implant in this same example, only if the aortic arch remains circular, the aortic arch radius is 15 mm and each arc length is 23.6 mm, as shown in FIG. 15C.

[0047]

[0074] Thus, the change in arc length from baseline (FIG. 15B) to post-implantation (FIG. 15D) is a 20% increase due to a 20% increase in radius, while other variables remain the same. In other words, each arc of the aorta is stretched by 20%. However, after insertion of the implant, the aortic arch does not remain circular. The radius of curvature of each arc increases, while at the same time the central angle corresponding to that arc decreases (see FIG. 23C). Although the opposing changes in these two variables confound an accurate estimate of the resulting arc length and degree of aortic arch stretch, this approach provides a reasonable and sufficient estimate of the resulting stretch in order to appropriately size the implant to achieve at least 20% stretch. Note that while the above analysis assumes a square cross section for the implant of FIG. 10A, this analysis can be modified to consider the implant of FIG. 11A, which divides the cross section into three equal parts, or the implant of FIG. 12A, which divides the cross section into five equal parts.

[0048]

[0075] Thus, by the above approach, the implant can be sized to provide at least 20% stretching of the target arterial wall. In some embodiments, the implant may be slightly larger to ensure at least 20% stretching, or to accommodate variations in aortic size, but still ensure at least 20% stretching in all cases. In some embodiments, the implant can be configured to provide additional stretching, e.g., 20-30%, 50% stretching, and even 100% stretching can be safely implemented in many patients.

[0049]

[0076] As previously mentioned, this design allows for the device to be deployed and stabilized at key anatomical targets within the vasculature. Preferably, this target location is within the aortic arch, stretching the aortic arch baroreceptors located along the cylindrical segment of the aortic arch (including along the inner curvature) that wraps the aorta between the origins of the left common carotid artery and the left subclavian artery from a human aortic arch CT angiography study. Although the aortic arch baroreceptors extend along the inner curvature of the aortic arch and circumferentially around the arch to the outer curvature or saddle region of the arch, the highest concentration of these baroreceptors is located on the segment adjacent to the left subclavian artery on the aortic arch that wraps the aorta along diameter C, shown as target T in FIG. 16. The implant configuration described herein is specifically configured to target this location, but also stretch the adjacent baroreceptors as safely as possible.

[0050]

[0077] V. Delivery and Placement in the Target Area In yet another embodiment, the implant device is particularly suitable for intravascular delivery and deployment because the implant has a collapsed configuration for advancement through the vasculature and an expanded configuration for engagement with the arterial wall, as shown in Figure 1. In the collapsed configuration, the implant is disposed within a delivery catheter to facilitate intravascular delivery and subsequent deployment to a target site in the aortic arch.

[0051]

[0078] In an exemplary embodiment, the implant is a self-expanding structure preloaded into a sheathed delivery catheter, as shown in FIG. 17. As shown, the intravascular delivery catheter is designed to deliver the implant in a folded configuration and position and deploy the implant at a target location, as shown in FIG. 16. The delivery catheter includes an internal guidewire lumen so that it can be advanced along a guidewire GW positioned in the aortic arch. In the illustrated embodiment, the delivery catheter 200 includes a catheter shaft 201 onto which the implant 100 is folded, and over which is disposed a retractable sheath 202 that restrains the implant in the folded configuration until the implant is positioned at the desired target location, for example, by visualization of a marker (e.g., a radiopaque or ultrasound marker). The marker can be a coating or marker attached to either or both of the connector and / or the expandable structure. In some embodiments, the connector may be made of a different material than the frame, so that the connector itself is clearly visible by visualization techniques. The delivery catheter may further include a distal tip 203 for guiding advancement across the GW and a flushing port 211 for flushing before, during, or after delivery. The delivery catheter includes a handle 210 that allows the clinician to retract the sheath to deploy the self-expanding implant. Typically, the overall length (l) of the delivery catheter is 100-150 cm (e.g., about 135 cm) for easy access to the aortic arch by inserting the catheter through the femoral artery.

[0052]

[0079] In some embodiments, the delivery catheter can be configured to deliver the entire implant upon retraction of the sheath, deploying both the first and second expandable structures in quick succession. The length of the expandable structures is sufficient so that the expandable structure 10 is deployed at the target location despite some small axial movement during deployment. Structure 20 is deployed first, but positioning and deployment is targeted to deploy structure 10 at the target location. In other embodiments, the delivery catheter can be configured to allow the sheath to be gradually retracted a specified distance to deliver the expandable structures sequentially, positioning the second, more distal structure first, then precisely positioning the first expandable structure at the target location, with the axially expandable connector providing some leeway in positioning the last deployed expandable structure. In still other embodiments, the implant may be balloon expandable and disposed in a folded configuration on a balloon of the delivery catheter, the balloon suitably dimensioned to expand within the aorta to expand and deploy the implant at the target area.

[0053]

[0080] Upon deployment, the implant, as shown in the exemplary embodiment of Figures 10A-12B, forms an open lattice with struts of the frame designed to stretch the aortic arch and stimulate the aortic arch baroreceptors, thereby reducing blood pressure, while exposing the arterial wall to each aortic pulsation through the large openings in the frame.

[0054]

[0081] 18A-18D show a sequence of steps of an exemplary method of treating hypertension by deploying an implant device described herein. As shown in FIG. 18A, a guidewire GW is advanced through an entry point (e.g., femoral artery) and advanced through the vasculature into the aortic arch. A visualization technique such as fluoroscopy can confirm placement of the GW in the target area. As shown in FIG. 18B, a delivery catheter 200 is advanced along the GW, the catheter having the implant 100 disposed in a folded configuration on the catheter shaft 201 and restrained within a retractable outer sheath 202. Once the implant is positioned at the desired target location within the aortic arch, as shown in FIG. 18C, the outer sheath 202 is retracted, thereby allowing the self-expanding implant 100 to elastically deploy into its expanded configuration with the two expandable structures 10, 20 engaging the arterial wall. The guidewire GW and delivery catheter 201 are then withdrawn, leaving the implant fixed at the target location in the aortic arch with at least one expandable structure 100 engaging and stretching the arterial wall in the target area for long-term reduction in blood pressure, as shown in FIG. 18D.

[0055]

[0082] 19 illustrates an exemplary method of treating hypertension with an implant device, comprising deploying an implant comprising one or more expandable structures along a target region of the aortic arch defined as a narrow band encasing the aorta between the LCCA and LSA, stretching the arterial wall along the target region by at least 20% with the struts of the implant, thereby inducing a baroreflex response, and exposing a majority of the stretched target region to pulsatile blood flow through large openings between the struts of the implant, thereby providing a long-term reduction in blood pressure.

[0056]

[0083] 20 illustrates another exemplary method of treating hypertension by deploying an implant in the aortic arch. The method includes deploying an implant comprising two or more expandable structures along a target region in the aortic arch, where at least one expandable structure engages the target region, stretching the arterial wall along the aortic arch by at least 15%, typically about 20%, with the struts of the implant, thereby inducing a baroreflex response and lowering blood pressure, exposing a majority of the stretched target region to pulsatile blood flow through large openings between the struts of the implant, thereby providing a long-term reduction in blood pressure, and long-term fixation of the implant to the target region with two or more expandable structures, where the expandable structures are interconnected in series by axially expandable connectors to accommodate the curvature and complex geometry of the aortic arch, thereby providing long-term fixation.

[0057]

[0084] 21A-1-21C-3 show alternative designs of expandable structures, each defined by one or more wires. Rather than a predefined frame joined along the sides as depicted in FIGS. 10A-13D, each expandable structure can be defined by one or more wires that define the design according to the required dimensions and characteristics of the implant. In some embodiments, the expandable structure can be formed from a single continuous wire that extends in a serpentine, sinusoidal or zigzag pattern to form a circumferential ring or band of the required dimensions to span the target area and exert sufficient outward force when expanded to stretch the arterial wall by a desired amount (e.g., about 20% or more). In some embodiments, the expandable structure is formed by two or more wires defined in such a pattern to form a circumferential ring or band of the required dimensions and to exert the required force. Typically, the wire is Nitinol and is set to a post-formation diameter that is sufficiently larger than the arterial diameter to stretch the artery to a target diameter to ensure sufficient stretching of the baroreceptors. The gauge of the wire can be selected to ensure that force requirements are met and to ensure the longevity of the implant. It is noted that in many such embodiments, the cross-sectional shape of these expandable structures is substantially circular such that the expandable structure uniformly increases the radius of the vessel wall, although the design still fully exposes the arterial wall to pulsatile forces after deployment.

[0058]

[0085] Three different designs (10A, 10B, and 10C) of expandable structures formed from wire (e.g., nitinol wire) are shown in Figures 21A-1-21C-3. Figures 21A-1-21C-1 show the structures at their post-formation diameter. Figures 21A-2-2 show the structures at their vessel diameter. Figures 21A-3-21C-3 show the structures in a constrained configuration for delivery to a target location within the aorta. In the illustrated embodiment, the designs are configured and sized to be deployed within the aortic arch. In some embodiments where the aorta has a vessel diameter in the range of 20-25 mm, the expandable structures can be configured to have a post-formation diameter of 35-40 mm, typically about 38 mm, and this study has shown that applying sufficient force to simulated vessels of these diameters to result in suitable stretching of the arterial wall (e.g., typically 20% or more). In these embodiments, the length l2 at the vessel diameter can range from 10 to 30 mm, typically 10 to 25 mm. In some embodiments, 10A has a length of about 23 mm, 10B has a length of about 17 mm, and 10C has a length of about 14 mm at the vessel diameter. In the constrained configuration, the lengths are slightly longer due to foreshortening effects (e.g., 24 mm, 18 mm, and 15 mm, respectively). In some embodiments, the wire diameter is 0.2 to 1.5 mm, typically 0.5 mm to 1 mm, and more typically about 0.6 mm.

[0059]

[0086] Studies were conducted using an embodiment of a wire construct similar to those in Figures 21A-1-21C-3 to demonstrate the viability of the implant in providing suitable stretching by increasing the diameter of the artery while still allowing sufficient compliance to maintain long-term efficacy. These studies were conducted in flexible 0.45 mm resin tubing fabricated to mimic the compliance and structure of the arterial wall in the aortic arch. The results of the studies are shown in Figure 22. The compliance of the 0.45 mm resin tubing was measured and recorded. An exemplary expandable construct was placed within the same 0.45 mm resin tubing and the resulting compliance (dashed line) was plotted along with the compliance of the empty tube (solid line). Both data sets were well fitted by linear regression with a second order polynomial.

[0060]

[0087] FIG. 22 demonstrates that the implant ring consistently stretches the plastic tube while maintaining compliance. For example, at a pressure of 50 mmHg, the implant ring increases the diameter from 20 mm to approximately 23 mm, i.e., a 15% stretch. Similarly, at a pressure of 200 mmHg, the implant ring increases the diameter from 25 mm to approximately 29 mm, i.e., a 16% stretch. The effect of the implant ring can also be interpreted in terms of pressure. For example, at a pressure of 100 mmHg, an empty tube (representing a native hypertensive vessel) has a diameter of approximately 21 mm. Placing an implant ring within this tube increases the diameter to approximately 24 mm, which corresponds to a pressure of 180 mmHg in the empty tube. In this scenario, the outward force of the implant ring corresponds to a static pressure of +80 mmHg. In this example, the baroreceptors are stimulated by a 15% stretch, or an equivalent pressure increase of +80 mmHg. It is therefore hypothesized that the implant ring will elicit a baroreceptor response consistent with such an increase in pressure, thereby reducing systemic pressure.

[0061]

[0088] It has been shown that acute stimulation of the baroreceptor reflex causes an immediate drop in systemic blood pressure, but that maintenance of pulsatility is required for a sustained response. Figure 22 also demonstrates that pulsatility of an empty tube (native vascular analog) is maintained with an implant ring in place (vascular analog treated with an implant ring). This is evident because the slopes of the compliance curves for the empty tube and the implant ring tube are substantially parallel. For example, at 100-200 mmHg, the empty tube pulsates between 21-25 mm (19%), while the same tube with an implant ring in place pulsates between 24-29 mm (21%).

[0062]

[0089] 23A-23B show another embodiment 120 utilizing multiple expandable structures 10, 20, 40, each with a wire design as in FIGS. 21A-21C, interconnected by a flexible connector 30. In this embodiment, D V indicates the nominal vessel diameter. D A is the active segment diameter, and D is the diameter at which the expandable construct is designed to apply the desired stretch while maintaining pulsatility. V Greater than. D D and D. P indicates the expanded diameter of the distal and proximal expandable structures, respectively. D D Maximum diameter and D P Each of the D Aor more. In some embodiments, the proximal and distal expandable structures can have a flared design to provide resistance to migration. In some embodiments, the expandable structures can include barbs or gripping coatings to resist migration. In some embodiments, the implant may be configured to be secured (e.g., by adhesives or coatings, etc.) after deployment to allow for repositioning during deployment. Flexible connectors or bridges connect the three expandable structures, each axially expandable or compressible, thereby allowing flexibility for the curve to conform to the shape of the arch. For example, the flexible connectors allow more extension / stretching at the outer radius and less extension or even compression along the inner radius of the arch, as shown in FIG. 23B.

[0063]

[0090] It is recognized that the expandable structures of these wire designs can also be utilized as the expandable structures of the implants of Figures 10-13 and can be similarly sized. For example, the central structure can be sized with a larger diameter than the proximal and distal structures, for example, 1.2-1.5 times larger diameter or maximum transverse dimension than the proximal and distal structures. It is further recognized that various flexible connector designs can be used. Figures 24A-24F depict various flexible connector designs including one or more sinusoids (as in Figure 24A), V-shaped sections (Figures 24B-24D), zigzag regions (Figure 24E) or coiled structures (as in Figure 24F) to allow axial expansion between adjacent rings or structures. It is recognized that although specific flexible connectors or bridges are depicted here, any suitable flexible connector can be used and the depicted bridge designs can be further extended to provide increased axial extension to better accommodate the aortic arch.

[0064]

[0091] VI. Design and Deployment of Alternative Implants As described in the previous embodiments, the implant device is hypothesized to utilize a circumferential stretch stimulus to activate the aortic baroreceptor nerves. However, it is recognized that axial stretch may also be relevant and can be utilized to provide additional activation of the baroreceptors. In some embodiments, the implant can be configured to stretch the arterial wall axially in addition to or instead of laterally.

[0065]

[0092] 25-26 depict an implant device configured to stretch the arterial wall circumferentially / laterally and axially, thereby providing additional activation of baroreceptors to further enhance the baroreflex response.

[0066]

[0093] As shown in FIG. 25, the implant 121 can include expandable structures of different configurations, with the middle expandable structure 40 providing circumferential (e.g., lateral) stretch as described throughout this application, and the connectors 30 to the proximal and distal expandable structures 10, 20 configured to provide axial stretch along the arterial wall. As in some previous embodiments, the design can be a three-structure design with proximal and distal anchoring structures and a middle active structure deployed at the target area. In this design, the flexible connectors (i.e., bridges) connecting the proximal and distal structures 10, 20 to the middle active structure 40 are configured as axial springs that are compressible to provide an axially directed force upon deployment.

[0067]

[0094] FIG. 26 shows a sequence of steps for deploying the implant of FIG. 25. In a first step, the distal structure 20 is deployed to a location distal to the target area. In a second step, the intermediate active structure 40 is deployed to the target area. However, when the intermediate structure 40 is deployed, the delivery catheter 200 is advanced distally to compress the axial spring between the distal structure 20 and the intermediate structure 40, axially loading the flexible connector to provide an axially directed stretching force to the arterial wall between the distal structure and the intermediate structure 40. In a third step, when the proximal structure 10 is deployed, the connector 30 between the intermediate structure 40 and the proximal structure 10 is compressed by pushing the delivery catheter again during deployment, whereby the compressed bridge connector provides an additional axially directed stretching force from the intermediate structure 40 to the proximal structure 10. Thus, this approach can not only provide circumferential stretch at the target region by the deployed intermediate active structure, but also axial stretch from the target region in both proximal and distal directions, thereby providing enhanced or potentially equivalent baroreceptor activation at a reduced implant diameter. Although specific designs are described herein, it will be recognized that a variety of other designs of connectors and / or proximal and distal expandable structures can provide axially directed stretching forces to enhance baroreceptor activation.

[0068]

[0095] Thus, the implant device and associated methods described herein address the unmet clinical need of treating patients with severe hypertension unresponsive to multiple pharmacological agents. Existing conventional treatments and therapies (e.g., renal denervation, carotid artery devices) have minimal or limited impact on this population due to their limited blood pressure lowering effect or risk of adverse events, respectively. The implants described herein are designed to meet this unmet clinical need based on historical and animal studies, as well as the identification of the unique anatomy and physiology of the aortic arch baroreceptors, and the CT angiography studies outlined above. The implants described herein allow for sufficient stretching of specific target areas of the aortic arch that triggers highly sensitive baroreceptors, thereby consistently and reliably lowering the patient's blood pressure while avoiding the adverse risks and drawbacks associated with conventional approaches that target other vasculature such as the carotid artery.

[0069]

[0096] Although the invention has been described in the foregoing specification with reference to specific embodiments thereof, those skilled in the art will recognize that the invention is not limited thereto. The various features, embodiments, and aspects of the invention described above can be used individually or together. Moreover, the invention can be utilized in any number of environments and applications beyond those described herein without departing from the broader spirit and scope of the present specification. Thus, the specification and drawings should be considered illustrative rather than restrictive. As used herein, it will be recognized that the terms "comprising," "including," and "having" are specifically intended to be read as open-ended technical terms. Unless otherwise specified, the term "about" is intended to mean within + / - 10%. Any reference to a publication, patent, or patent application is incorporated herein by reference in its entirety for all purposes.

Claims

1. 1. A method for treating hypertension in a patient, comprising: deploying an implant within the patient's aortic arch, the implant comprising a plurality of expandable structures interconnected by flexible connectors, each of the plurality of expandable structures having an expanded configuration and a collapsed configuration, in the collapsed configuration the implant is advanceable through the vasculature, and in the expanded configuration the implant engages an arterial wall of the aortic arch; stretching at least a portion of the arterial wall along a target region of the aortic arch by engagement of a first of the plurality of expandable structures, thereby eliciting a baroreflex response of baroreceptors in the target region; exposing a majority of the arterial wall along the target area to pulsatile blood flow through a plurality of large openings in the expandable structure so as to sustain the baroreflex response induced by the implant for a long period of time; A method comprising:

2. The method of claim 1 , wherein the portion of the arterial wall is stretched by at least 20%.

3. The method of claim 1 , wherein the target region is a cylindrical segment encompassing the aortic arch between the LCCA and the LSA.

4. 2. The method of claim 1, wherein each expandable structure includes one or more wires defining a design having a length greater than its transverse dimension, and the implant is deployed such that the length of the expandable structure extends in the direction of blood flow along the aorta.

5. The method of claim 4 , wherein each expandable structure comprises a single continuous Nitinol wire.

6. The method of claim 1 , wherein each expandable structure is defined by a laser cut design in a single tube.

7. The method of claim 1 , wherein each expandable structure has a circular cross-section.

8. The method of claim 4 , wherein the implant comprises three such expandable structures interconnected in series by the plurality of flexible connectors.

9. 2. The method of claim 1, wherein each expandable structure includes a plurality of elongate frames having a length greater than its lateral dimension, and the implant is deployed such that the lengths of the plurality of elongate frames extend in the direction of blood flow along the aorta.

10. 10. The method of claim 9, wherein each frame includes a pair of struts defining opposite sides of the frame and spaced apart a distance sufficient to stretch the portion of the arterial wall engaged by the pair of struts by at least 20% when the implant is deployed.

11. The method of claim 10, wherein each expandable structure comprises three to five frames interconnected along adjacent sides thereof to form a regular polygonal cross-section.

12. The method of claim 11, wherein the struts are spaced apart a distance of between 20mm and 40mm to define large openings therebetween.

13. The method of claim 12 , wherein the straight struts have a length of about 40 mm or greater.

14. maintaining blood flow to one or more lateral arteries branching from the aortic arch through one or more large openings in the first and / or second expandable structures of the plurality of deployed implants. The method of claim 1 further comprising:

15. maintaining the position of the deployed implant along the target region for an extended period of time by deploying a second of the plurality of expandable structures into an adjacent region of the aortic arch such that engagement of the first and second expandable structures against the arterial wall together secures the implant from dislodging. The method of claim 1 further comprising:

16. maintaining said position and adapting to the curvature of the aortic arch by expansion of the flexible connector, the flexible connector extending axially a greater distance near the outer curvature of the aortic arch than one or more flexible connectors along the inner curvature of the aortic arch. The method of claim 15 further comprising:

17. maintaining said position selecting the implant from a set of implants having different dimensions of the first and second expandable structures based on measurements of the patient's aortic arch morphology obtained from a computed tomography angiogram; The method of claim 15 further comprising:

18. Preventing trauma to the arterial wall during deployment and long-term implantation in the aortic arch with proximal and distal atraumatic crowns of each frame, the proximal atraumatic crown connecting proximal ends of the pair of struts and the distal atraumatic crown connecting distal ends of the pair of struts of the respective frame, the atraumatic crowns comprising an arc of less than a semicircle. The method of claim 1 further comprising:

19. 1. An implant for treating hypertension in a patient, comprising: a plurality of expandable structures interconnected in series by flexible connectors, the expandable structures having a collapsed configuration for advancement through the patient's vasculature and an expanded configuration for engagement of an arterial wall within the patient's aortic arch; Equipped with the flexible connector is axially expandable to accommodate the aortic arch when the plurality of expandable structures are deployed within the aortic arch; wherein at least one of the expandable structures is dimensioned such that when expanded within a target region of the aortic arch, the expandable structure increases a blood vessel diameter sufficiently to elicit a baroreflex response of baroreceptors in the target region while sufficiently exposing the arterial wall in the target region to pulsatile blood flow to sustain the baroreflex response for an extended period of time. Implant.

20. 20. The implant device of claim 19, wherein the at least one expandable structure is dimensioned such that arterial tissue engaged by a pair of struts stretches the arterial wall at least 20% between the struts.

21. The implant device of claim 19, wherein the at least one expandable structure is dimensioned to have a maximum lateral dimension of between 25 mm and 60 mm.

22. The implant device of claim 19, wherein the at least one expandable structure is dimensioned to have a maximum lateral dimension of between 30 mm and 40 mm.

23. 20. The implant device of claim 19, wherein the at least one expandable structure is dimensioned with a length of about 40 mm or greater to ensure engagement of the target area.

24. 20. The implant device of claim 19, wherein each of the expandable structures is sized with a length of about 40 mm or more and a maximum lateral dimension of 30-40 mm.

25. The implant device of claim 19 , wherein each of the expandable structures has the same dimensions.

26. The implant device of claim 19 , wherein the plurality of expandable structures have different dimensions.

27. 20. The implant device of claim 19, wherein the flexible connector is axially expandable to allow the implant to conform to the curvature of the aortic arch.

28. The implant device of claim 19 , wherein the implant is self-expanding.

29. 30. The implant device of claim 28, wherein the implant is formed at least in part from Nitinol.

30. 20. The implant device of claim 19, wherein the implant is balloon expandable.

31. 20. The implant device of claim 19, wherein each expandable structure includes one or more wires defining a design having a length greater than its lateral dimension, and the implant is deployed such that the length of the expandable structure extends in the direction of blood flow along the aorta.

32. 32. The implant device of claim 31, wherein each expandable structure comprises a single continuous Nitinol wire.

33. 20. The implant device of claim 19, wherein each expandable structure is defined by a laser cut design in a single tube.

34. The implant device of claim 19 , wherein each expandable structure has a circular cross-section.

35. 20. The implant device of claim 19, wherein the implant comprises three such expandable structures interconnected in series by the plurality of flexible connectors.

36. Each expandable structure of the plurality of expandable structures comprises: a plurality of elongated frames, each frame defining opposing sides and having a pair of struts spaced to define a large opening therebetween, said frames interconnected along adjacent sides to form a regular polygonal cross section of said implant; 20. The implant device of claim 19, comprising:

37. 20. The implant device of claim 19, wherein each of the plurality of expandable structures includes four frames interconnected to form a square cross-section.

38. 20. The implant device of claim 19, wherein each of the plurality of expandable structures includes three frames interconnected to form a triangular cross-section.

39. 20. The implant device of claim 19, wherein each of the plurality of expandable structures includes five frames interconnected to form a pentagonal cross-section.

40. 20. The implant device of claim 19, wherein each frame includes proximal and distal atraumatic ends that respectively interconnect the proximal and distal ends of a pair of struts to avoid trauma to arterial tissue during delivery, deployment and long-term implantation.

41. 41. The implant device of claim 40, wherein the proximal and distal atraumatic ends comprise an arc of less than half a circle.

42. 20. The implant device of claim 19, further comprising one or more markers visible by visualization techniques during delivery to facilitate positioning of the implant device at the target area within the aortic arch.

43. 43. The implant device of claim 42, wherein the one or more markers include radiopaque or ultrasound visible markers disposed on the plurality of flexible connectors.

44. 20. The implant device of claim 19, wherein the plurality of expandable structures comprises three expandable structures, an intermediate structure configured to deploy at the target area and proximal and distal expandable structures configured to provide anchoring of the intermediate structure at the target area.

45. 45. The implant device of claim 44, wherein the intermediate structure has a lateral dimension greater than a lateral dimension of each of the proximal and distal expandable structures.

46. 46. ​​The implant device of claim 45, wherein the lateral dimensions of the intermediate expandable structure are 1.3 to 1.5 times greater than the lateral dimensions of the proximal and distal expandable structures.

47. 45. The implant device of claim 44, wherein the flexible connector includes an axially compressible spring, the spring causing the implant to provide axial stretching of the arterial wall upon deployment.

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