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Future of Hypertension

2019; Lippincott Williams & Wilkins; Volume: 74; Issue: 3 Linguagem: Inglês

10.1161/hypertensionaha.119.13437

1524-4563

Victor J. Dzau, Celynne A. Balatbat,

Cardiovascular Health and Risk Factors

HomeHypertensionVol. 74, No. 3Future of Hypertension Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBFuture of HypertensionThe Need for Transformation Victor J. Dzau and Celynne A. Balatbat Victor J. DzauVictor J. Dzau Correspondence to Victor J. Dzau, National Academy of Medicine, 500 Fifth Street NW, Washington, DC 20001. Email E-mail Address: [email protected] From the Office of the President, National Academy of Medicine (formerly the Institute of Medicine), Washington, DC. Search for more papers by this author and Celynne A. BalatbatCelynne A. Balatbat From the Office of the President, National Academy of Medicine (formerly the Institute of Medicine), Washington, DC. Search for more papers by this author Originally published29 Jul 2019https://doi.org/10.1161/HYPERTENSIONAHA.119.13437Hypertension. 2019;74:450–457Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 29, 2019: Ahead of Print Hypertension is one of the most pressing public health challenges. It is recognized as the biggest contributor to the global burden of disease. Globally, in 2015, 1.13 billion adults had raised blood pressure (defined as systolic blood pressure [SBP] of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher).1 In 2015, over 19% of all deaths were linked to elevated SBP (>115 mm Hg).2The global burden of hypertension has been growing over time, largely driven by population growth, changes in lifestyle, and aging. The number of adults with raised blood pressure (defined as SBP of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher) increased from 594 million in 1975 to 1.13 billion in 2015, with the increase largely in low- and middle-income countries.1 Approximately 75% of people with hypertension (1.04 billion) live in low- and middle-income countries.3 Likewise, deaths from elevated SBP grew by an average of 1.6% per year between 1990 and 2015. When stratified by developmental status as measured by the sociodemographic index, countries with lower developmental status showed greater increases in the number of deaths linked to elevated SBP than the most developed countries. The largest percent increase deaths related to elevated SBP between 1990 and 2015 occurred in low-middle countries (107%).2Alarmingly, hypertension is controlled in less than a fifth of patients worldwide.4 Furthermore, there are vast global disparities in hypertension awareness, treatment, and control, with challenges that are particularly acute in low- and middle-income than in high-income countries. According to 2010 data, compared with low- and middle-income countries, high-income countries had proportionately double the awareness (67.0% versus 37.9%) and treatment (55.6% versus 29.0%) and 4× the control among patients with hypertension (28.4% versus 7.7%).3Detecting hypertension early and taking measures to control it may be a cost-effective way to reduce the hypertension-related disease burden. However, many challenges exist, beginning with early detection and ongoing follow-up. Hypertension is often referred to as the silent killer because there are often no symptoms or warning signs. As a result, it is critical to check blood pressure regularly. Yet, there is no easy way to measure blood pressure. The diagnosis of hypertension is still based primarily on measurement using a cuff. Once hypertension is diagnosed, treatment can be life long, regimens are relatively arbitrary and not precise, and often comes with side effects. Effective, inexpensive blood pressure–lowering drugs are offered to, and regularly used by, only a fraction of the patients who need them. In addition, as discussed below, the guidelines for treatment—based on data from RCTs (randomized controlled trials—have many problems. Finally, diagnosis based on blood pressure measurements alone neglects the many factors that influence blood pressure: social, behavioral, dietary, physical activities, other variables. Finally, the pathophysiology and genetics of primary or essential hypertension (defined as hypertension that does not have a secondary cause) remain unclear.Need for TransformationDespite the huge public health burden and sustained research efforts focused on hypertension, we have seen slow progress in global control of hypertension. Transformation is urgently needed to reduce the global burden of hypertension.Hypertension has been studied in a large number of clinical trials. A search on http://www.clinicaltrials.gov yielded 7190 studies on hypertension as of March 11, 2019. Indeed, over the years, a significant number of pivotal studies in the field of hypertension have been conducted and their results published, from the Veterans Administration Cooperative Studies (1960s) to SPRINT (Systolic Blood Pressure Intervention Trial) and ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) in recent years. Furthermore, there have been substantial research on regulators and mediators of blood pressure, the pathophysiology and genetics of essential hypertension.5–7In spite of these efforts, recent research has not yielded major advances in hypertension. There have not been new targets identified for hypertension drug development. In fact, trends show a dramatic slowing of research and development for novel hypertension drugs. The reasons are multifold—the field is crowded with relatively effective drugs, there is a lack of major new discoveries and targets, and there are many challenges in developing blockbuster drugs. While advances in genomics have yielded insights into the monogenic and polygenic determinants of blood pressure regulation and variation; and researchers have identified over 500 single nucleotide polymorphisms associated with blood pressure and over 32 genes associated with monogenic forms of hypertension; these advances are still awaiting entry into clinical applications. We have not seen the development of any blockbuster drug for hypertension in recent decades and pharmaceutical companies have largely abandoned the search for a one.8Reversing these trends and achieving meaningful improvement in hypertension control and management will necessitate a transformative system-wide, cross-sector approach across many key areas: biomedical, digital, data, implementation, and population sciences (Table).Table. Meaningful Improvement in Hypertension Control and Management Requires a Transformative System-Wide, Cross-Sector ApproachDigital transformationData science transformation and artificial intelligenceBiotech and biomedical transformationHealthcare delivery transformationPopulation science transformationDigital TransformationMany emerging technologies are already transforming health care—changing the way care is delivered, when care is delivered, who care is delivered by, and where care is delivered. The overall trend is a shift away from the hospitals and clinics with care delivered in daily settings, such as the home, and a greater focus on prevention.In particular, chronic diseases that require regular follow-up and therapeutic adjustments can benefit from effective utilization and integration of technology-based tools. Already, we have seen much progress in the use of digital health/technology for diabetes monitoring and control. In 2016, the number of diabetes care apps on the Apple App Store and Google Play Store reached nearly 1800.9The total revenue for the digital diabetes market tripled to $98 million in 2017.9 Bundled sales of digitally connected diabetes products and service are predicted to take off up to $742 million by 2022.10Although the large volume of diabetes apps does not mean that all of them are effective, it, nevertheless, indicates the significant opportunities for digital technologies as potential solutions. This should hold true for hypertension, with promising new digital technologies to enable home blood pressure measurement that can be transmitted directly to health providers and the electronic medical record. However, we have seen comparatively little progress for hypertension, which has a greater global burden: 422 million people had diabetes mellitus in 2014 according to the World Health Organization; versus 1.13 billion adults with hypertension in 2015.11 According to mHealth Economic 2017, the top 3 fields with the best market potential for digital health solutions are diabetes mellitus, followed by obesity and depression.12It is clear that hypertension is behind and needs to enter the digital age. In particular, there is a need for digital health interventions to enable home blood pressure measurement, promote guideline and treatment adherence, and promote healthy behaviors such as increased physical activity and better diets.Automated blood pressure devices with remote data transmission to providers or the electronic health record have been shown to be useful in improving hypertension control in clinical trials,13–15 yet automated home blood pressure monitoring is not routinely used in practice.Importantly, research indicates that ambulatory blood pressure data provide a more comprehensive assessment of blood pressure over the course of a day and have been reported to better predict health outcomes than blood pressure measured in the clinic (clinic blood pressure).16–18 For example, a study of 115 708 people found that 39% of people who had normal blood pressure readings at the doctor office had high blood pressure readings out of the office over a 24-hour period. Under European blood pressure criteria, 20% had high blood pressure when performing out-of-office readings.19 This phenomena, known as masked hypertension has important implications for health outcomes. An analysis of data from nearly 64 000 adults in a registry-based, multicenter, national cohort found that ambulatory blood pressure measurements were a stronger predictor of all-cause and cardiovascular mortality than clinic blood pressure measurements.20In recent years, many digital health interventions (from apps to internet-based tools) have emerged that give patients access to health information and encourage behavior change by offering incentives and personalized feedback. Digital health tools that encourage patients to increase their physical activity and eat healthier diets may be important tools in managing hypertension. More research is needed in this promising area.An area in need of major advancement is the development of easy to use, accurate, and reproducible, cuffless blood pressure measurement. The traditional cuff-based blood pressure (BP) measurement is nonspontaneous, labor intensive, and time consuming. The ability to monitor BP in real time that is digitally connected to clinical decision and other data sets can be transformative in enabling early detection, monitoring and control, and management in the context of multiple factors influencing BP and related risks.There has been some progress in the development of home blood pressure/cuffless measurement devices. The most advanced technologies on noninvasive continuous BP measurement are tactile sensing, vascular unloading technique, pulse transit time, photoplethysmography, ultrasound-based BP measurement, and BP measurement from image processing.21Examples of recent promising technologies for noninvasive blood pressure measurement include: Omron Heartguide, which has an extra-stiff band that inflates to measure BP like a normal blood pressure cuff as well as Checkme cuffless blood pressure monitoring device based on pulse transit time.22,23 Both devices are able to synchronize data with smartphone apps.Several smartwatches that measure BP have also been introduced, such as the Heartisans Blood Pressure Watch (Heartisans, Hong Kong, Hong Kong) or the BPro device (HealthSTATS Technologies, London, United Kingdom).24We are likely to see further developments in this area, with major companies entering the field. Last year, Samsung announced a collaboration with the University of California, San Francisco, to develop the My BP Lab application, which uses a built-in optical sensor in the Galaxy S9 mobile phone to measure BP via pulse transit time.25In spite of these developments, noninvasive, continuous BP measurement technologies require further development and refinement to make them reliable, accurate, and user friendly. Virtually, all available noninvasive continuous BP measurement technologies have limitations or shortcomings. For example, BP measurement using image processing is highly dependent on the device characteristics; therefore, overall accuracy tends to suffer.Other cuffless monitors, such as those based on photoplethysmography, must be calibrated using a cuff-based measurement.26 Moreover, more work is needed to evaluate the device in a hypertensive population.27In the future, other technologies such as small, wearable, patches based on ultrasound technology may be used to noninvasively and continuously measure blood pressure. Last year, researchers engineered a wearable ultrasound patch that can noninvasively monitor blood pressure in arteries far beneath the skin and can be worn as a flexible skin patch.28For now, further research is needed to ensure the accuracy of new BP monitoring devices, assess the feasibility in different settings, evaluate such devices in a hypertensive population, and ensure that such devices are affordable and easy to use.The development or new BP monitoring technologies is especially important in light of the low rates of hypertension awareness and control globally. Noninvasive, continuous BP monitoring technology could improve hypertension detection and awareness by providing measurements across the entire population during daily life and enhance hypertension control by providing continual feedback to individual patients.16,29Data Science Transformation and Artificial IntelligenceThe collection and integration of vast amounts of data will transform hypertension research, management, and control. Massive amounts of health, social, and personal data are being generated and captured in real time. This real-world evidence will play a critical role in the development of a learning health system. The ability to integrate this data from disparate sources and analyze it will enable us to better understand patterns of disease and drivers of health, especially the role of environmental factors or the social determinants of health on hypertension.In recent years, advances in genomics and other omics have ushered in a precision medicine revolution. Thus far, precision medicine has largely focused on genomics, an approach that is likely to yield advances in the diagnosis and treatment of rare diseases and cancer. However, hypertension does not have a single identifiable cause; there is a strong genetic component with its pathophysiology varying greatly from individual to individual. In addition, responses to hypertension medications differ among individual patients. As a result, improving hypertension control may require individualized therapies and treatment for different patients.30The combination of advances in genomics and other omics with broader insights from data science and other fields holds promise for hypertension. A broader precision medicine, data-driven revolution has the potential to transform our understanding of the environmental factors and lifestyle modifications on the development of hypertension and to enable precise, personalized care. Such an approach may eventually result in the development of wholly new targets for the prevention and treatment of hypertension.This precision medicine data revolution, driven by a convergence of biological, physical, engineering, computer, health, and social sciences, is setting the stage for a transformative leap toward data-driven, mechanism-based health and health care for each individual.The creation of precision cohorts (using big data) is particularly important for hypertension. Hypertension has been studied in a large number of RCTs. Most of today’s approach to hypertension management especially treatment guidelines are derived from interpretation of the data from RCTs. The problem with this is that RCTs often do not take into account the diversity of real lives. Recent analysis of RCTs has revealed many different subgroups with important differences. Yet, recommended treatment/guidelines are based on the mean results of RCTs and expert consensus. There is a need for big data and real-time evidence.Recently, inconsistencies in the results of major RCTs of hypertension demonstrate the importance of taking into account the diversity of real lives. Two large randomized trials, ACCORD and SPRINT, the effect of treating patients with high BP and high cardiovascular disease risk who received intensive therapy (SBP target <120 mm Hg) or standard therapy (SBP target <140 mm Hg). The results of the 2 trials differed in their CVD mortality outcomes. In the ACCORD study, patients randomly assigned to intensive therapy, compared with standard therapy, did not have reductions in the primary composite outcome of CVD events. In SPRINT, patients randomly assigned to intensive therapy had both clinically and statistically significant reductions in CVD events and CVD mortality. Although the relative risk reduction in CVD events observed in the trials (12% in ACCORD versus 25% in SPRINT) did not differ significantly, differences in the relative risk reduction in CVD mortality were statistically significant (6% increase in ACCORD versus 43% decrease in SPRINT; P<0.05). The inability to identify why the ACCORD and SPRINT results differ illustrates the limitations of conventional treat-to-target trials as they often do not provide reliable evidence to decipher heterogeneous treatment effects—or to identify whether and why some patients vary in their response to a treatment decision.To examine the discrepancies between ACCORD and SPRINT, Basu et al performed a theoretical modeling study, demonstrating that trial designs using sequential randomization are much better at detecting heterogeneous treatment effects. They found that increasing harm at low diastolic BP ( 3 agents, may explain differences in the results of SPRINT and ACCORD. Uncovering heterogeneous treatment effects is critical because benefit and risk assessments are required to ensure that individual patients receive the benefits observed in SPRINT while avoiding the potential harms observed in ACCORD.31Another transformative opportunity for hypertension management and control is the advent of artificial intelligence (AI) in health care. In the near future, AI has the potential to revolutionize hypertension treatment and control. AI, which refers to the science and engineering of making intelligent machines, especially intelligent computer programs32 and includes machine learning, natural language processing, deep learning and other related applications, is poised to transform all of health care—this holds true for hypertension. Although AI applications in hypertension are still in their infancy, AI has the potential to revolutionize hypertension through improved access and better monitoring, better prediction to guide treatment, improved clinical decision-making, better adherence to guidelines, patient engagement, and the development of new insights into the pathogenesis of hypertension.Patient facing technologies that are based on AI could facilitate increased access to care, better treatment adherence, and even virtual health coaching. For instance, the use of AI chatbots could be used to augment the existing healthcare workforce, expanding access to care for patients. At Geisinger Health in Pennsylvania, an AI chatbot has been used to provide patients with the results of their exome sequencing, reducing the need for genetic counselors.33In the future, AI-based technologies may even enable patients to take care into their own hands. Already, the Food and Drug Administration has approved a smartwatch algorithm to detect atrial fibrillation as well as the Apple Watch’s ECG and irregular rhythm notification functions. Other AI-based smartphone apps are being developed to diagnose medical conditions such as, skin lesions and rashes, ear infections, migraine headaches, and retinal diseases such as diabetic retinopathy and age-related macular degeneration. Other AI-based smartphone apps monitor medication adherence, requiring patients to take a video of them swallowing their prescribed medication. Indeed, AI-based virtual assistants may help patients manage chronic conditions, such as hypertension, in the future.Applying AI to multimodal data, such as diet, physical activity, sleep, gut microbiome activity, medications, and more, could generate insights and guide/promote healthy behaviors and appropriate treatment. With the ubiquity of smart speakers (such as Amazon Alexa), smartphones, and wearables (such as the Apple Watch), it is easy to envision that such coaching could be provided continuously to individuals in the areas where they live, work, and play—enabling a holistic, preventive approach.33Many factors contribute to poorly controlled BP, including biological, environmental, and lifestyle issues. AI may help facilitate new insights from large and diverse datasets to inform prescribers and patients about specific factors (eg, biological, lifestyle, environmental) that may contribute to the development of hypertension and impact BP control. AI could also be used to enable the identification of novel genotypes.Biotechnological and Biomedical TransformationFor those patients who either do not tolerate or wish to take medication for hypertension or in whom BP control is not attained despite multiple antihypertensives, many new interventional procedures to manage hypertension have emerged, such as renal denervation, baroflex activation therapy, carotid body ablation, deep brain stimulation, arteriovenous fistula, neurovascular decompression, and renal artery stenting. Most of these new devices are supported by early and encouraging evidence from early phase trials for both safety and efficacy. However, the data from the Medtronic phase 3 study on renal denervation failed to show a significant reduction in the interventional group as compared with control.34 Currently, additional studies are being conducted to evaluate the efficacy of renal denervation. Importantly, it is not clear if or which of the effects of interventional therapies are sustained over time. Thus, it is clear that rigorous clinical trial data will be essential before any of the technologies can be adopted as a standard of care.With regard to novel biopharmaceutical entities for hypertension treatment, as discussed earlier, pharmaceutical companies have not focused substantial attention to the development of new hypertension drugs. According to Pharmaceutical Research and Manufacturers of America, in 2018, biopharmaceutical research companies were developing 200 medicines for cardiovascular disease—14 of which were for hypertension; in comparison, 42 were for heart failure.35 Moreover, it is important to note that many new drugs and devices in development have shown initial promise, yet have not been able to survive the development process and make it to patients. Finally, many successful drugs and devices are likely to be directed toward a relatively small minority of the hypertensive population because of costs.With the promise of precision medicine, there remains the potential of developing safer and more effective drugs for specific populations. Furthermore, biotechnology is advancing at rapid speed and novel approaches are being discovered that can change the approach to treatment from traditional drugs and devices.Indeed, new technologies hold promise for the development of breakthrough hypertension treatments. Some of these technologies may exert long-lasting effects, which may make treatment simpler and efficient.Here, we will review targeting treatment using novel RNA, DNA, or cell-based therapies.RNA InterferenceRNA interference (RNAi) is a promising strategy for new hypertensive agents. RNAi is a naturally occurring regulatory mechanism to silence gene expression. RNAis are short RNAs that activate ribonucleases to target homologous mRNA resulting in the silencing of a specific gene.36 RNAi is an important tool for researchers to learn about the function of a gene but also for therapeutic intervention—to target diseases that may result from undesirable activity of a gene.Already, RNAi has been used successfully for cardiovascular research and is being evaluated for human therapy. For example, RNAi has been used to target PCSK9 (proprotein convertase subtilisin/kexin type 9), a recently identified but well-validated target for low-density lipoprotein cholesterol–lowering therapy. PCSK9, an enzyme expressed and secreted into the bloodstream predominantly by the liver, plays an important role in cholesterol metabolism and also seems to modulate hypertension.37,38 Of note, PCSK9 loss-of-function mutations are associated with low circulating low-density lipoprotein cholesterol levels and diminished cardiovascular risk with no apparent negative health consequences. In phase 2 clinical trial, RNAi has been shown to significantly reduce levels of PCSK9 and low-density lipoprotein cholesterol in humans for 6 months of follow-up.39 This is proof of concept that RNAi can be an effective modality for long-term treatment of cardiovascular disease.As for hypertension, example of an important therapeutic target is angiotensinogen, the sole substrate of the renin-angiotensin system. Studies have demonstrated a relationship between angiotensinogen and hypertension, suggesting that decreased production of angiotensinogen may be a useful target for novel hypertension drugs.40–42 One can envision an RNAi approach targeting angiotensinogen in the liver, the main production site of circulating angiotensinogen. Indeed, researchers have already shown that siRNA can be used to reduce angiotensinogen production in the liver of rats, which resulted in decreased plasma angiotensinogen and decreased blood pressure in both hypertensive and normotensive rats. These results were sustained suggesting that this treatment would not need to be administered daily.43 However, further research is needed to examine efficacy and safety for humans.Gene Editing—Somatic Gene Editing of PCSK9Another promising strategy is the use of genome editing to target genes for human hypertension therapy. Similar to the use of RNAi, researchers have already demonstrated that CRISPR-Cas9 genome editing technology can be used to effectively target mouse PCSK9 in vivo as well as in authentic human hepatocytes in vivo in a liver-humanized mouse model.44 In addition, researchers editing monkeys’ genomes in their livers reduced the animals’ blood cholesterol levels. Wang et al45 showed that single infusions in nonhuman primates of adeno-associated virus vector expressing an engineered meganuclease targeting PCSK9 results in dose-dependent disruption of PCSK9 in liver, as well as a stable reduction in circulating PCSK9 and serum cholesterol. PCSK9 levels dropped by as much as 84% and low-density lipoprotein levels dipped as much as 60% in treated monkeys.45These results suggest that PCSK9-targeting genome-editing therapies could be effective in humans. However, further research will be needed to prevent off-target effects, unwanted immune effects, and validate the efficacy of the technology in clinical trials.In the future, genome editing (using CRISPR-Cas9) holds promise for curing genetic hypertension, and in targeting angiotensinogen and other targets, resulting in possible long-term control of essential hypertension.Regenerative Medicine—Treating the Complications of HypertensionHypertension is associated with complications such as thrombotic and hemorrhagic stroke, retinopathy, acute myocardial infarction and heart failure, proteinuria and renal failure, and atherosclerotic vascular disease including stenoses and aneurysms.46 Organ damage with irreversible loss of functional tissue can lead to end organ failure. The heart and brain have limited capacity for regeneration after damage. New regenerative medicine strategies including stem cell therapy, cellular reprogramming, and tissue engineering hold promise for tissue regeneration and restoration of function after myocardial infarction and stroke.One approach is stem cell therapy, which aims to reduce cardiac degeneration by regenerating cardiomyocytes. Stem cells are undifferentiated cells theoretically capable of renewing themselves indefinitely under appropriate conditions through mitotic cell division, and can maintain, generate, or replace damaged tissue by differentiating into specialized cell types. Researchers are studying different types of stem cells to repair damaged heart muscle, including embryonic stem cells, adult stem cells, and induced pluripotent stem cells.Different strategies have been developed to enhance cardiac regeneration. First is the use of cell therapy involving the injection of adult progenitor cells from bone marrow, adipose tissue, and myocardium into ischemic hearts in human clinical trials. The studies have yielded unimpressive results. Investigators have also attempted the use of mesenchymal stem cells or cardiospheres, but the results too have been disappointing. Studies have demonstrated that the injected cells engraft poorly and exhibit poor viability after transplantation. The use of induced pluripotent stem cell holds promise but are still in the experimental stage.Given the challenges of cell th