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      Protective Effects of Nanoparticle-Loaded Aliskiren on Cardiovascular System in Spontaneously Hypertensive Rats

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          Abstract

          Aliskiren, a renin inhibitor, has been shown to have cardioprotective and blood pressure (BP) lowering effects. We aimed to determine the effects of nanoparticle-loaded aliskiren on BP, nitric oxide synthase activity (NOS) and structural alterations of the heart and aorta developed due to spontaneous hypertension in rats. Twelve week-old male spontaneously hypertensive rats (SHR) were divided into the untreated group, group treated with powdered or nanoparticle-loaded aliskiren (25 mg/kg/day) and group treated with nanoparticles only for 3 weeks by gavage. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions, and collagen content were determined in both the heart and aorta. Vasoactivity of the mesenteric artery and wall thickness, inner diameter, and cross-sectional area (CSA) of the aorta were analyzed. After 3 weeks, BP was lower in both powdered and nanoparticle-loaded aliskiren groups with a more pronounced effect in the latter case. Only nanoparticle-loaded aliskiren increased the expression of nNOS along with increased NOS activity in the heart (by 30%). Moreover, nanoparticle-loaded aliskiren decreased vasoconstriction of the mesenteric artery and collagen content (by 11%), and CSA (by 25%) in the aorta compared to the powdered aliskiren group. In conclusion, nanoparticle-loaded aliskiren represents a promising drug with antihypertensive and cardioprotective effects.

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          The use of human umbilical vein endothelial cells (HUVECs) as an in vitro model to assess the toxicity of nanoparticles to endothelium: a review.

          With the rapid development of nanotechnologies, nanoparticles (NPs) are increasingly produced and used in many commercial products, which could lead to the contact of human blood vessels with NPs. Thus, it is necessary to understand the adverse effects of NPs to relevant cells lining human blood vessels, especially endothelial cells (ECs) that cover the lumen of blood vessels. Human umbilical vein endothelial cells (HUVECs) are among one of the most popular models used for ECs in vitro. In the present review, we discussed studies that have used HUVECs as a model to investigate the EC-NP interactions, the toxic effects of NPs on ECs and the mechanisms. The results of these studies indicated that NPs could be internalized into HUVECs by the endocytosis pathway as well as transported across HUVECs by exocytosis and paracellular pathways. Exposure of HUVECs to NPs could induce cytotoxicity, genotoxicity, eNOS uncoupling and endothelial activation, which could be explained by NP-induced oxidative stress, inflammatory response and dysfunction of organelles. In addition, some studies have also evaluated the influences of microenvironment (e.g. the presence of proteins and excessive nutrients), the physiological and/or pathological stimuli related to the diversity of ECs (e.g. shear stress, cyclic stretch and inflammatory stimuli), and the physicochemical properties of NPs on the responses of ECs to NP exposure. In conclusion, it has been suggested that HUVECs could be considered as a relatively reliable and simple in vitro model for ECs to predict and evaluate the toxicity of NPs to endothelium. Copyright © 2017 John Wiley & Sons, Ltd.
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            PLGA Nanoparticles in Drug Delivery: The State of the Art;

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              An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention

              Cardiovascular diseases, including heart disease, hypertension and heart failure, along with stroke, continue to be leading causes of death in the United States. 1,2 Hypertension currently affects nearly 78 million* adults in the United States and is also a major modifiable risk factor for other cardiovascular diseases and stroke. 1 According to data from the National Health and Nutrition Evaluation Survey (NHANES) in 2007–2010, 81.5% of those with hypertension are aware they have it, and 74.9% are being treated but only 52.5% are under control, with significant variation across different patient subgroups. 1,3–6 Of those with uncontrolled hypertension, 89.4% reported having a usual source of health care, and 85.2% reported having health insurance. 7 This is the current status, despite the fact that therapies to lower blood pressure and associated risks of cardiovascular events and death have been available for decades and various education and quality improvement efforts have been targeted at patients and healthcare providers. The direct and indirect costs of hypertension are enormous, considering the number of patients and their families impacted as well as the healthcare dollars spent on treatment and blood pressure-related complications. 8 Currently, hypertension affects 46% of patients with known cardiovascular disease, 72% of those who have suffered a stroke, and was listed as a primary or contributing cause in approximately 15% of the 2.4 million deaths in 2009. 1 In 2008, the total estimated direct and indirect cost of hypertension was estimated at $69.9 billion. 8 Thus, it is imperative to identify, disseminate and implement more effective approaches to achieve optimal control of this condition. High-quality blood pressure management is multifactorial and requires engagement of patients, families, providers and healthcare delivery systems and communities. This includes expanding patient and healthcare provider awareness, appropriate lifestyle modifications, access to care, evidence-based treatment, a high level of medication adherence and adequate follow-up. 9 Recognizing the urgent need to address inadequate control, the American Heart Association (AHA) has made hypertension a primary focus area of its 2014–2017 strategic plan as it seeks to improve the cardiovascular health of all Americans by 20% and reduce the death rate from cardiovascular disease and stroke by 20% by 2020. 10 Similarly, Million Hearts, a US Department of Health and Human Services initiative spearheaded by the Centers for Disease Control (CDC) and Prevention and the Centers for Medicare & Medicaid Services (CMS) to prevent a million heart attacks and strokes by 2017, has focused its first 2 years on actions to improve and achieve control of hypertension. 11 We believe that identification of best practice, evidence–based management algorithms leading to standardization of treatment is a critical element in helping to achieve these ambitious national goals at a population level. In this paper, we describe the value of hypertension treatment algorithms, provide criteria for effective hypertension management algorithms, describe an AHA/American College of Cardiology (ACC)/CDC-recommended treatment algorithm based on current guidelines and describe examples of other specific algorithms that have been associated with improved blood pressure on a large scale. The Value of Hypertension Treatment Algorithms As Part of a Multifactorial Approach to Improve Blood Pressure Control As described previously, despite the strong evidence and consensus regarding the treatment and control of high blood pressure, 9,12 as well as the availability of many different therapeutic options, achieving success in hypertension control at both the individual patient-level and even more importantly, the population-level, has remained a major challenge nationally. Although there is no single explanation for the poor hypertension control seen in many patient subgroups, the fragmentation of health care for many patients and the lack of consistent implementation of system-level solutions in clinical practice and healthcare delivery systems appear to be important contributors. Efforts focused primarily on educating patients and providers about hypertension and the benefits of its treatment have not been sufficient in bringing hypertension under control. Similarly, interventions targeting only physicians have not led to consistent and meaningful improvements on a large scale. 13 However, there are examples of substantial success that could be emulated and scaled with a high likelihood of important benefit. To reduce the prevalence of hypertension in the United States, 10,14 system-level approaches will be needed. Successful examples from other medical areas where a system-level approach has been taken include reducing medical errors and improving patient safety in the hospital setting 15 ; improving the inpatient treatment and outcomes of acute myocardial infarction, heart failure, stroke and cardiopulmonary resuscitation 16 ; reducing health disparities in the treatment of cardiovascular conditions 16 ; early detection and intervention in sepsis to lower case fatality 17,18 ; and reducing hospital-acquired infections. 19,20 In the case of hypertension, system-level methods can address multiple factors in a coordinated manner: Identifying all patients eligible for management Monitoring at the practice/population level Increasing patient and provider awareness Providing an effective diagnosis and treatment guideline Systematic follow-up of patients for initiation and intensification of therapy Clarifying roles of healthcare providers to implement a team approach Reducing barriers for patients to receive and adhere to medications as well as to implementing lifestyle modifications Leveraging the electronic medical record systems being established throughout the US to support each of these steps Several examples of success using a system-level paradigm have been recently reported. For example, within Kaiser Permanente Northern California, a large integrated healthcare delivery system caring for >3 million members, a regional hypertension program was implemented involving five major components: creation and maintenance of a health system-wide electronic hypertension registry, tracking hypertension control rates with regular feedback to providers at a facility- and provider-level, development and frequent updating of an evidence-based treatment guideline, promotion of single-pill combination therapies and using medical assistants for follow-up blood pressure checks to facilitate necessary treatment intensification. Between 2001 and 2009, the number of patients with hypertension increased from 349,937 to 652,763, but the proportion of hypertensive patients meeting target blood pressure goals improved substantially from 44% to >80%, and continued to improve to >87% in 2011. 21 Favorable hypertension control rates have been observed in other healthcare delivery systems 22 as well as coordinated health systems such as the Veterans Affairs medical system. 23–25 Developing, disseminating and implementing an effective hypertension treatment algorithm is a critical part of a multipronged, systematic approach to controlling hypertension, as it facilitates clinical decision-making, provides a default approach with proven benefits, and engages multiple providers in a coordinated manner. We describe next the principles for developing such an algorithm. Principles for Algorithm Development The following is a summary of principles recommended by the AHA, ACC, and CDC for creating an effective hypertension management algorithm: Base algorithm components and processes on the best available science. Format to be simple to update as better information becomes available. Create feasible, simple implementation strategy. Include patient version at appropriate scientific and language literacy level. Consider costs of diagnosis, monitoring, treatment. Develop algorithm in format easily used within a team approach to health care. Develop algorithm in a format able to be incorporated into electronic health records for use as clinical decision support. Include a disclaimer to ensure that the algorithm is not used to counter the treating healthcare provider’s best clinical judgment. The purpose of these principles is to establish a common platform for the development and implementation of hypertension management algorithms tailored to different practice settings and populations. We note the last principle supports the notion that treatment guidelines serve to facilitate a systematic approach to the management of hypertension, but provide appropriate modifications based on specific patient characteristics, preferences and other pragmatic factors (eg, cost, pill burden, risks of certain side effects) to optimize a personalized approach to the care of individual patients. 9,12,26,27 In addition, ongoing randomized clinical trials (eg, SPRINT 28 ) are addressing optimal blood pressure targets for specific patient subgroups such as the elderly and patient with chronic kidney diseases to maximize net clinical benefit and avoid unnecessary complications. AHA/ACC/CDC Hypertension Treatment Algorithm In the Appendix is a template outlining a general approach for an effective treatment algorithm that incorporates the principles described previously and balances applicability the largest number of hypertensive patients with the flexibility and the level of detail to support individualization of therapy. Several existing algorithms for hypertension treatment in large healthcare settings associated with improved blood pressure in populations 21 have also been reviewed, which included a look at both private and public systems, systems with regional reach, as well as an algorithm used by the US Department of Veteran Affairs that are in support of the recommended principles. These algorithms are either attached in the online-only data supplement or are available for public use within the resources and tools section of the Million Hearts initiative Web site at http://millionhearts.hhs.gov/resources.html. Call-to-Action, Next Steps, and Conclusions It is critical that the AHA, ACC and CDC, together with other organizations, continue to identify, define, and implement exemplary local, regional, and national programs that facilitate better blood pressure awareness, treatment, and control together with improving other cardiovascular health factors and behaviors. 11,15,29–31,31a Arming healthcare providers, health systems, and communities with proven tools, algorithms, strategies, programs, and other best practices along with expertise and technical assistance for improving blood pressure awareness, treatment, and control is essential to reducing the tremendous burden of cardiovascular risk. 30,32 This advisory serves as a call to action for broad-based efforts to improve hypertension awareness, treatment, and the proportion of patients treated and controlled. There is a clear need to provide enhanced, evidence-based, blood pressure treatment systems for providers, including standardization of protocols and algorithms, incentives for improved performance based on achieving and maintaining patients at blood pressure goals, and technology-facilitated clinical decision support and feedback. 32 As noted previously, health system wide implementation of focused evidence-based hypertension treatment algorithms together with regularly scheduled performance feedback within a coordinated multifactorial management program have been associated with substantially improved hypertension control in large populations and varied clinical practice settings. 21,32–34 This approach can facilitate the ability to emphasize existing evidence-based recommendations and integrate new evidence as it becomes available. Successful best practices or innovations can be further identified and then disseminated health system wide. 21 Such an approach is scalable, sustainable, and of high value, especially as the use of electronic medical records becomes even more widespread nationally. 21,33,34,40 This advisory has provided a number of examples of algorithms from successful programs that can be readily implemented in diverse healthcare settings. Greater participation in innovative programs such as the AHA’s Heart 360 personal health record, 35 AHA/ASA’s Get With The Guidelines Program, 36 the AHA/ADA/ACS Guideline Advantage Program, 37 and the HHS Million Hearts initiative, 11,15,30,31 as well as the ACC’s National Cardiovascular Data Registries (NCDR) 38 and CDC Coverdell Stroke registry, 39 should also be encouraged and incentivized. Further engaging individuals in the hypertension control process, motivating more proactive management though shared accountability and incentives for blood pressure treatment and control are also essential. 30 There are also opportunities for the increased role of pharmacists and other community-based providers in hypertension treatment and control. 30,40,41 There is also great potential to apply an innovative mix of health information technology, peer support, feedback, and incentive programs designed to drive actionable, patient-centered blood pressure awareness, treatment and control programs. Workplace and community based wellness programs can also have significant impact. 30 It is also vital that these programs are implemented among broader segments of the population. Disparities/inequities in hypertension awareness, treatment, and control continue to exist in a number of patient subgroups. 6,42 Intervention programs for hypertension should be specifically targeted to groups with the greatest cardiovascular risk and disease burden based on clinical risk factors and appropriate consideration of sex, race, ethnicity, socioeconomic status, disability, and geographic location. 30 Additional research is needed to better define blood pressure treatment goals especially in specific populations including by age, sex, race, ethnicity, and comorbid conditions. It is essential that there be proportionate representation of these patient populations in the study of blood pressure goals as well as new hypertension treatment technologies such as catheter-based renal sympathetic denervation. The AHA, ACC, CDC, and other organizations should continue to foster effective activities regarding hypertension which include surveillance, education and media, organizational partnerships, and environmental and policy changes. 30 Building on such programs as the AHA’s Life’s Simple 7 program 43 with a longitudinal cardiovascular health tracking system, patient-oriented clinical decision support tool, individual patient-oriented cardiovascular health performance measures, and data feedback, and ACC’s CardioSmart Patient Education Portal 44 with a customized patient dashboard for blood pressure management, an interactive workbook to educate and motivate better health, and a patient text messaging program providing heart healthy tips aimed at primary prevention should be considered within a comprehensive system-level management program. This approach may help to facilitate and incentivize improvement in blood pressure control, cardiovascular health, as well as enhance real-time surveillance of cardiovascular health. Further research efforts to enhance specific interventions for improving patient adherence and to identify optimal patient-centered, value oriented systems of care should continue to be supported. This advisory is intended to complement and support clinical guidelines, providing clinicians and health systems tools to improve treatment and control of hypertension. The prevention of heart disease and stroke mandates a greater emphasis on the population-wide improvement of blood pressure awareness, treatment, and control together with other cardiovascular health factors. 15,26,45 Supplementary Material 1
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                25 July 2019
                August 2019
                : 24
                : 15
                : 2710
                Affiliations
                [1 ]Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Sienkiewiczova 1, 813 71 Bratislava, Slovakia
                [2 ]Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, 040 01 Kosice, Slovakia
                Author notes
                [* ]Correspondence: olga.pechanova@ 123456savba.sk ; Tel.: +421-2-3229-6020
                Author information
                https://orcid.org/0000-0003-0132-670X
                Article
                molecules-24-02710
                10.3390/molecules24152710
                6695910
                31349653
                0d163fbf-bd5d-408d-b595-70ce73a4df97
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 May 2019
                : 22 July 2019
                Categories
                Article

                hypertension,renin,aliskiren,nitric oxide,heart,aorta,vasoactivity,collagen,pla nanoparticles

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