A Compendium on Hypertension: New Advances and Future Impact.

Abstract

HomeCirculation ResearchVol. 128, No. 7A Compendium on Hypertension Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessReview ArticlePDF/EPUBA Compendium on HypertensionNew Advances and Future Impact Rhian M. Touyz and Ernesto L. Schiffrin Rhian M. TouyzRhian M. Touyz Correspondence to: Rhian M. Touyz, MD, PhD, Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Pl, Glasgow, G12 8TA. Email E-mail Address: [email protected] https://orcid.org/0000-0003-0670-0887 Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow (R.M.T.). Search for more papers by this author and Ernesto L. SchiffrinErnesto L. Schiffrin https://orcid.org/0000-0002-4502-2823 Lady Davis Institute for Medical Research, Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, QC, Canada (E.L.S.). Search for more papers by this author Originally published1 Apr 2021https://doi.org/10.1161/CIRCRESAHA.121.319181Circulation Research. 2021;128:803–807The population burden of hypertension was initially highlighted over 45 years ago1 and since then almost 10 000 articles in Pubmed have been published with key words hypertension and burden. With hypertension the major cause of morbidity and mortality worldwide,2,3 the personal, societal, and health burden of high blood pressure remains a reality. Exacerbating this situation are declining trends in blood pressure control in patients with hypertension4,5 and the potential impact on hypertension and cardiovascular risk of coronavirus disease 2019 (COVID-19).6,7 Accordingly, it is not surprising that there have been many national and international Calls to Action to address hypertension as a health priority including the recent 2020 US Surgeon General’s call to control hypertension.8–10Hypertension CompendiumThe evidence that normalization of blood pressure is accompanied by beneficial clinical outcomes is unequivocal. This was already evident in the 1960s, when data from the pioneering Framingham Heart Study clearly showed that elevation in blood pressure was tightly linked to an increased risk of illness and death from cardiovascular disease.11 More recently, findings from the SPRINT (Systolic Blood Pressure Intervention Trial) revealed that more intensive lowering of blood pressure to levels below previously recommended values was associated with significantly reduced rates of cardiovascular events and risk of death.12 Numerous clinical trials have demonstrated efficacy of the different classes of antihypertensive drugs.13Why then does hypertension remain sub-optimally controlled and how do we explain that in 2021 the silent killer still remains the major cause of morbidity and mortality worldwide? This Hypertension Paradox of more uncontrolled hypertension despite improved therapies, defined by Chobanian in the 2009 Shattuk lecture14 is multifactorial and likely relates, at least in part, to gaps in knowledge about the causes, mechanisms, and complex interplay between modifiable and nonmodifiable risk factors. Nonetheless, there has been major progress in the field to address the gaps and to advance knowledge so that hopefully it will not be too long before the burden of hypertension is reduced. The present Compendium on Hypertension is a collection of state-of-the-art reviews by experts in the field including a wide range of topics spanning population health to molecular mechanisms to artificial intelligence and focuses on new concepts, recent advances, and future impact. It is a follow-up of the 2015 and 2019 Hypertension Compendia in Circulation Research, with the aim of providing new topics and advancements in the field to complement and build upon those previously published.15,16For many years, hypertension has been considered a clinical problem primarily in high-income countries. However more recently, it has emerged that over 30% of adults in low- and middle-income countries are hypertensive, contributing to the global pandemic of hypertension. Unless effective measures are put into place, the trajectory of increasing blood pressure will continue. Schutte et al17 discuss the reasons behind the growing trend in low- and middle-income countries and suggest some novel solutions in a region-specific context. In addition, they introduce some of the global initiatives in place to address the issue, including the WHO HEARTS Technical Package. Managing hypertension in different regions involves diverse strategies.Fundamental to best clinical practice is evidence-based medicine, lessons learned from clinical trials and user friendly, and appropriate guidelines. Carey et al18 present a comprehensive update on modern evidence-based hypertension guidelines. They contextualize the findings of relevant observational studies, randomized clinical trials, and meta-analyses that have been published between January, 2018 and March, 2021. In particular, they highlight practical topics including blood pressure measurement, patient evaluation for secondary hypertension, and cardiovascular disease risk assessment. Additionally, important issues related to management are presented including blood pressure thresholds for drug treatment, lifestyle and pharmacological management, treatment blood pressure goals, management of hypertension in older adults, diabetes, chronic kidney disease, resistant hypertension, and optimization of care using patient, provider, and health system strategies. This inclusive review should help to increase hypertension awareness, and improve treatment and control, which are essential for prevention of cardiovascular disease.To effectively treat hypertension in a disease- and a targeted-specific manner, it is essential to understand the molecular mechanisms and pathophysiological processes that underlie blood pressure elevation. However, this is complicated because hypertension is a multifactorial disorder involving multiple interlinked physiological systems and organs, numerous cell types, myriad sub-cellular processes, and innumerable signaling pathways and networks. This complexity was already appreciated in the 1940s when Dr Page developed the Mosaic Theory of Hypertension19 advocating that hypertension is the result of many factors that interact to raise blood pressure and cause end-organ damage. The original mosaic comprised genetic, environmental, anatomic, adaptive, endocrine, humoral, and hemodynamic factors. With new discoveries, it became clear that other factors are also important including sodium homeostasis, oxidative stress and inflammation, and the microbiome. The complexity continues to expand and many novel systems and factors have recently been discovered that further define the mosaic as discussed by Harrison et al.20 In this issue, they appraise the interdependency between the various elements and nodes of the mosaic and provide a provocative discussion on the interpretation of data in the context of experimental models.The importance of the vascular system and kidneys in the pathophysiology of hypertension has long been recognized, with ongoing debate whether hypertension is primarily a disorder of the vascular system or the kidneys.21–23 More recently other systems have been suggested to be central players including the immune system.24 What is clear is that all physiological systems are interlinked and that perturbed cross-talk between systems contributes to development of hypertension. In this issue, Boutouyrie et al25 provide an update on arterial stiffness in the pathophysiology of hypertension. They highlight the notion that structural stiffness predicts outcomes in models that adjust for conventional risk factors and propose that arterial stiffness measurement should be a keystone in hypertension management and cardiovascular prevention. Some new insights on mechanisms that contribute to arterial stiffness during the course of aging and hypertension are discussed, and the potential impact of antihypertensive therapy on reversing vascular remodeling and improving cardiovascular health is suggested.Expanding on new concepts in pathophysiological systems, Sequeira-Lopez and Gomez26 introduce the notion that renin-producing cells play an important role in regulating intrarenal arteries and kidney function. In this comprehensive review, they discuss molecular mechanisms that control the fate of renin-producing cells, highlight their pleiotropic nature, and discuss how these unique cells have evolved to adapt to homeostatic threats and stresses. During development renin producing cells are progenitors involved in the morphogenesis of the renal arterial tree whereas in adulthood they are involved in blood pressure regulation, fluid-electrolyte balance, and tissue perfusion. Many of these processes involve the renin-angiotensin system, salt and inflammation, which influence the immune system in hypertension. Madhur et al27 advance these concepts and discuss how chronic overactivation of immune cells, especially T cells, influences tissue damage, and development of hypertension. They suggest that factors that impact the gut microbiome are central to the immune responses contributing to blood pressure elevation. Molecular mechanisms that activate T cells and how they infiltrate tissues to produce cytokines causing renal and vascular dysfunction and target organ damage in hypertension are discussed. Supporting the notion that the microbiome is important in immune activation and hypertension, Avery et al28 remind us that the gastrointestinal tract houses the largest compartment of immune cells in the body and represents the intersection of the environment and the host. In this issue, they provide an up-to-date appraisal of the role of the microbiome in the pathophysiology of hypertension and discuss pharmacological and lifestyle-centred strategies targeting the microbiome as an emerging potential therapy in cardiovascular medicine.Hypertension is closely associated with other comorbidities especially overweight and obesity. Together, these comorbidities add to the growing global burden of cardiovascular and metabolic disease. A common factor underlying these comorbidities is adipose tissue, which is a highly dynamic organ that undergoes expansion and remodeling and produces adipokines, vasoactive peptides and inflammatory mediators that influence cardiovascular function. Koenen et al29 address the abnormal remodeling of specific adipose tissue depots during obesity and how this contributes to the development of hypertension, endothelial dysfunction, and vascular stiffness. They also delineate the local and systemic roles of adipose tissue-derived secreted factors and increased systemic inflammation in obesity and highlight their detrimental impact on cardiovascular health. New insights on the vasoprotective effects of brown adipose tissue and the injurious vascular effects of white adipose tissue in different adipose depots are described, providing new insights into potential beneficial effects of brown adipose tissue.Advances in molecular biology, proteomics, cell biology, imaging, systems biology, big data, and experimental medicine approaches have enabled discovery of new mechanisms of disease in hypertension. Highlighted in the present compendium are some of these exciting new paradigms. Cicalese et al30 develop the concept that hypertension results from chronic physiological maladaptation against stressors including circulating or local neurohormonal factors, mechanical stress, intracellular accumulation of toxic molecules, and dysfunctional organelles. They discuss the role of endoplasmic reticulum stress, oxidative stress, metabolic mitochondrial stress, DNA damage, stress-induced senescence, and proinflammatory processes. Highlighted in this review are some common adaptive signaling mechanisms against these stresses including unfolded protein responses, antioxidant response element signaling, autophagy, mitophagy, and mitochondrial fission/fusion, signaling effector stimulator of interferon genes-mediated responses, and activation of pattern recognition receptors. Recent advancements in stress-adaptive signaling mechanisms, as well as potential therapeutic targets, are discussed. Griendling et al31 further develop the concept that oxidative stress is fundamental to many of the cell stressors in hypertension and discuss new advances in mechanisms of oxidative stress, redox signaling, and clinical implications. They emphasize the importance of endoplasmic reticular stress and mitochondrial oxidative stress and discuss the emerging field of oxidative redox proteomics in hypertension.Fang et al32 examine the role of nuclear receptors as ligand-activated transcription factors that act as sensors to make cell adaptations by mediating changes in gene expression. They focus on PPARs, a family of orphan receptors, and particularly on PPARγ (peroxisome proliferator-activated receptor gamma), the isoform implicated as an important regulator of blood pressure. PPARγ, influences blood pressure by modulating renal, vascular, and immune function. Impaired PPARγ function promotes hypertension as indicated in genetic studies where PPARγ mutations cause hypertension. They provide clinical trial evidence that PPARγ activators have beneficial effects on blood pressure and suggest that future research should focus on developing these agents as safe potential therapeutic vasoprotective and antihypertensive agents.Drug-induced hypertension is an unappreciated cause of secondary hypertension.33 Many commonly used drugs such as nonsteroidal anti-inflammatory agents, pseudoephedrine-containing decongestants, cyclosporine, and others have long been known to increase blood pressure.33 More recently, it has become evident that anticancer drugs, especially VEGF (vascular endothelial growth factor) inhibitors, cause an elevation in blood pressure. Of significance, over 80% of patients with cancer treated with antiangiogenesis drugs demonstrate an increase in blood pressure and ≈40% become hypertensive. Emerging evidence indicates that this phenomenon extends beyond VEGF inhibitors. Accordingly, while new chemotherapies prolong cancer survival this may be at an increased risk of hypertension and associated cardiovascular morbidities. van Dorst et al34 highlight the implications of this upward trend and the potential impact on cardiovascular health in cancer survivors. They also delineate the growing number of antineoplastic drugs that cause hypertension and elucidate potential underlying mechanisms. This article highlights hypertension at the interface of cardiovascular medicine and oncology (cardio-oncology), emphasizing the need for collaborative clinical care between cardiologists, hypertension specialists, and oncologists. It also underlines the importance of mechanistic research and clinical trials to provide evidence-based information so that anticancer effects of novel chemotherapies are maximized while minimizing cardiovascular risk.Emerging new factors that will likely influence the future impact of hypertension is COVID-19. Hypertension is both a risk factor and consequence of COVID-19 with recent studies indicating that young patients with hypertension and obesity are especially at increased risk of severe COVID-19 disease.35–37 Processes linking cardiovascular disease to COVID-19 are elusive, although it has been suggested that the renin-angiotensin system, and especially ACE (angiotensin-converting enzyme) 2, the receptor via which SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) enters cells, may be important. Savoia et al38 update us with the epidemiological and clinical data linking hypertension and COVID-19 and critically discuss the notion that inhibitors of the renin-angiotensin system could have adverse effects in patients with COVID-19. The authors review current data on the role of hypertension and its management in patients with COVID-19 and also how COVID-19 affects hypertension management.Despite the many effective antihypertensive drugs currently available worldwide, hypertension control remains sub-optimal. To address this, there have been numerous efforts made to develop novel and alternative approaches for the management of hypertension, including device-based technologies. In this issue, Mahfoud et al39 discuss interventional therapies, based in large part on targeting the sympathetic nervous system. The newer technologies that have emerged are aimed at modulating the peripheral nervous system, including renal denervation, baroreflex activation therapy, endovascular baroreflex amplification therapy, carotid body ablation, and pacemaker-mediated programmable hypertension control. Of these, renal denervation is the most advanced in development, with encouraging results from new clinical trials. This approach shows great promise.Exciting new strategies to improve diagnosis and management of hypertension are discussed by Padmanabhan et al.40 They highlight the potential utility of artificial intelligence and machine learning. This is a very exciting area that will certainly impact the way clinicians manage patients with hypertension. The authors discuss the challenges and opportunities in advancing these technologies and development of algorithms and highlight the importance of validation of these approaches.Together this collection of outstanding reviews provides the reader with new insights in the field of experimental and clinical hypertension research. These articles will allow readers to have a fresh look at hypertension, from genetics to mechanisms to diagnosis and management, demonstrating that the science of hypertension and related cardiovascular disease is in constant evolution, and that we are headed to discovery of novel approaches that will contribute to improve outcomes for hypertensive patients. We hope that they will also stimulate new basic, clinical, epidemiological, and health services research and further progress in the management of high blood pressure.Nonstandard Abbreviations and AcronymsACE2angiotensin-converting enzyme 2COVID-19coronavirus disease 2019SPRINTSystolic Blood Pressure Intervention TrialVEGFvascular endothelial growth factorSources of FundingR.M. Touyz is supported by grants from the British Heart Foundation (RE/18/6/34217, CH/4/29762). E.L. Schiffrin’s research is supported by Canadian Institutes of Health Research (CIHR) First Pilot Foundation Grant 143348 and a Distinguished James McGill Professor Award.Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 806.Correspondence to: Rhian M. Touyz, MD, PhD, Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Pl, Glasgow, G12 8TA. Email rhian.[email protected]ac.uk