Table of Contents

INTRODUCTION          10

WHAT IS NEW AND WHAT HAS CHANGED IN THE 2023 EUROPEAN SOCIETY OF HYPERTENSION ARTERIAL HYPERTENSION GUIDELINES?          12

1. Methodology and definition of evidence          14

 1.1 Methodology of evidence grading          14

 1.2 Level of evidence          14

2. PRINCIPLES OF HYPERTENSION PATHOPHYSIOLOGY          16

3. DEFINITION OF HYPERTENSION AND BP CLASSIFICATION          18

 3.1 Definition of hypertension          18

 3.2 Classification of hypertension          19

 3.3 Prevalence of hypertension          20

 3.4 BP relationship with risk of cerebral, cardiovascular and kidney events          20

 3.5 Hypertension and total CV risk assessment          21

 3.6 Screening versus case finding in the detection of hypertension          24

 3.7 Confirming the diagnosis of hypertension          25

4. BP MEASUREMENT AND MONITORING          26

 4.1 Devices for blood pressure measurement          26

  4.1.1 Standard cuff-based devices          26

  4.1.2 Cuffless blood pressure measuring devices          27

  4.1.3 Validation of blood pressure measuring devices          27

 4.2 Standard office blood pressure measurement          28

 4.3 Unattended office blood pressure measurement          30

 4.4 Blood pressure during exercise          32

 4.5 Blood pressure measurement in hospital          32

 4.6 Central blood pressure          33

 4.7 Home blood pressure monitoring          34

 4.8 Ambulatory blood pressure monitoring          36

 4.9 Clinical indications for HBPM and ABPM          39

 4.10 Blood pressure variability          41

5. PATIENT WORK-UP          42

 5.1 Personal and medical history          42

 5.2 Physical examination          44

 5.3 Routine clinical chemistry investigations          45

 5.4 Other investigations in hypertension          45

  5.4.1 Electrocardiogram          45

  5.4.2 Kidney ultrasound          46

  5.4.3 Selected biomarkers and genetic markers          46

   5.4.3.1 Lipoprotein (a)          46

   5.4.3.2 Cardiac biomarkers          46

   5.4.3.3 Kidney markers          47

   5.4.3.4 Genetic markers          47

5.5 Assessment of hypertension-mediated organ damage          48

  5.5.1 HMOD in the heart          49

   5.5.1.1 Left ventricular mass and geometry          50

   5.5.1.2 Transthoracic echocardiography          50

   5.5.1.3 Cardiac magnetic resonance          51

   5.5.1.4 Computed tomography of the heart          52

  5.5.2 HMOD in the arteries          52

   5.5.2.1 Carotid artery IMT and plaques          52

   5.5.2.2 Pulse wave velocity          53

   5.5.2.3 Ankle–brachial index          55

  5.5.3 HMOD in the kidney          55

  5.5.4 HMOD in the brain          56

  5.5.5 HMOD in the eye          58

 5.6 Using HMOD to help stratify risk in hypertensive patients          60

 5.7 When to refer a patient to a specialist or for hospital-based care          62

6. SECONDARY HYPERTENSION          63

 6.1 Genetic causes of secondary hypertension          67

7. LIFESTYLE INTERVENTIONS          69

 7.1 Relevance of lifestyle changes          69

 7.2 Weight reduction          70

 7.3 Restriction of sodium intake          70

 7.4 Augmentation of dietary potassium intake          71

 7.5 Increase levels of daily physical activity and regular exercise          72

 7.6 Moderation of alcohol intake          73

 7.7 Smoking cessation          74

 7.8 Other dietary interventions          75

 7.9 Improve stress management          75

 7.10 Exposure to noise and air pollution          76

8. BENEFITS OF ANTIHYPERTENSIVE TREATMENT          77

9. ANTIHYPERTENSIVE DRUG TREATMENT INITIATION          79

 9.1 Should treatment initiation be based on total CV risk?          79

 9.2 Office BP thresholds for initiation of drug treatment          79

 9.3 Should BP-lowering treatment be initiated in patients with office BP <140/90 mmHg?          81

 9.4 Drug treatment initiation in older people          82

10. OFFICE BP TARGETS FOR TREATMENT          85

 10.1 Office BP targets in the general hypertensive population          85

 10.2 Office versus home and ambulatory BP targets          87

 10.3 Timing of BP control and time in therapeutic range          88

 10.4 Residual risk          88

 10.5 Challenges associated with evidence on BP targets          89

11. ANTIHYPERTENSIVE DRUGS AND TREATMENT          92

 11.1 Blockers of the renin–angiotensin system          96

  11.1.1 Angiotensin-converting-enzyme inhibitors          96

  11.1.2 Angiotensin receptor blockers          96

  11.1.3 Renin inhibitors          96

  11.1.4 Combination of RAS inhibitors          97

 11.2 Calcium channel blockers          97

  11.2.1 Dihydropyridine CCBs          97

  11.2.2 Nondihydropyridine CCBs          97

 11.3 Diuretics          97

  11.3.1 Thiazide and Thiazide-like diuretics          97

  11.3.2 Loop diuretics          99

  11.3.3 Potassium-sparing diuretics          99

 11.4 Mineralocorticoid receptor antagonists          99

 11.5 Beta-blockers          100

 11.6 Alpha-1 blockers          102

 11.7 Centrally acting drugs          103

 11.8 Vasodilators          103

 11.9 Angiotensin receptor-neprilysin inhibitor          103

 11.10 Antihypertensive drug combinations          104

  11.10.1 Impact on hypertension drug treatment strategy          104

  11.10.2 Drug combinations          106

  11.10.3 Rationale for initial two-drug combination therapy          110

  11.10.4 Up-titration of treatment to three-drug combination          112

  11.10.5 Rationale for single-pill combination therapy          112

  11.10.6 The quadpill concept          113

  11.10.7 The polypill concept          114

  11.10.8 Choice of drug combinations for initiation of treatment          115

  11.10.9 Tolerability and side effects of drugs          115

  11.10.10 Prescribing of antihypertensive drugs          116

   11.10.10.1 Standard drug administration          116

   11.10.10.2 Partial treatment reduction or complete withdrawal          117

   11.10.10.3 Antihypertensive drugs and cancer risk          118

   11.10.11 Concomitant medications          119

   11.10.11.1 LDL-cholesterol lowering          119

   11.10.11.2 Antiplatelet therapy          121

 12. TRUE RESISTANT HYPERTENSION          122

  12.1 Definition, prevalence, pathophysiology and cardiovascular risk          122

  12.2 Diagnostic work-up          123

  12.3 Optimizing lifestyle interventions and ongoing drug therapy          125

  12.4 Fourth and subsequent lines of antihypertensive therapy          126

 13. DEVICE-BASED TREATMENT OF HYPERTENSION          131

  13.1 Renal denervation          131

   13.1.1 Clinical evidence of the BP-lowering effect of RDN          131

   13.1.2 Off-medications studies          132

   13.1.3 On-medications studies          132

   13.1.4 Safety          133

   13.1.5 Durability          134

   13.1.6 Application          134

  13.2 Carotid baroreceptor stimulation          136

  13.3. Other device-based treatments          136

 14. SPECIFIC HYPERTENSION PHENOTYPES          137

  14.1 Sustained hypertension and true normotension          137

  14.2 White-coat hypertension          138

  14.3 Masked hypertension          139

  14.4 White-coat uncontrolled hypertension and masked uncontrolled hypertension          141

  14.5 Isolated systolic hypertension of the young          142

  14.6 Isolated systolic hypertension in older persons          144

  14.7 Isolated diastolic hypertension          146

  14.8 Night-time hypertension and dipping          147

  14.9 Orthostatic hypertension and hypotension          149

  14.10 Baroreflex failure and efferent autonomic failure          150

 15. HYPERTENSION IN DIFFERENT DEMOGRAPHIC SITUATIONS          152

  15.1 Blood pressure in children, adolescents and transition period          152

   15.1.1 Blood pressure measurements in children and adolescents          152

   15.1.2 Hypertension in children and adolescents          153

   15.1.3 Transition period to adulthood          154

  15.2 Hypertension in young adults          155

  15.3 Hypertension in older persons          156

   15.3.1 Patients 65–79 years old          157

    15.3.1.1 Threshold and target for drug treatment          157

    15.3.1.2 Antihypertensive treatment strategies          158

    15.3.1.3 Antihypertensive drugs          158

    15.3.1.4 Monitoring the effects of treatment          159

   15.3.2 Patients 80 years old or beyond          159

   15.3.3 How to assess the level of frailty/functionality to better personalize therapeutic strategies          160

 15.4 Sex and gender aspects in hypertension          163

  15.4.1 Epidemiology and pathophysiology          163

  15.4.2 Blood pressure and cardiovascular risk          164

  15.4.3 Differences in clinical phenotypes          164

   15.4.3.1 White-coat hypertension and masked hypertension          164

   15.4.3.2 Hypertension-mediated organ damage          164

  15.4.4 Sex differences in hypertension outcomes          165

  15.4.5 Benefits of antihypertensive treatment and target blood pressure          166

  15.4.6 Sex differences in hypertension management          167

  15.4.7 Infertility treatments and hypertension in women          167

  15.4.8. Oral contraceptive pills and hypertension          168

  15.4.9 Hormone-replacement therapy and hypertension          169

  15.4.10 Gender-affirming hormone therapy and hypertension          169

  15.5 Hypertension and ethnicity          169

   15.5.1 Nomenclature and relevance          169

   15.5.2 Management          170

 16. HYPERTENSION IN SPECIFIC SETTINGS          171

  16.1 Hypertension disorders in pregnancy          171

  16.1.1 Definition and classification of hypertension in pregnancy          173

  16.1.2 Blood pressure measurement in pregnancy          174

  16.1.3 Laboratory examinations in pregnancy          175

  16.1.4 Prediction and prevention of preeclampsia          175

  16.1.5 Lifestyle interventions          176

  16.1.6 Clinical management of hypertension in pregnancy          176

   16.1.6.1 Mild preexisting essential hypertension          176

   16.1.6.2 Mild gestational hypertension          177

   16.1.6.3 Preeclampsia          178

   16.1.6.4 Severe hypertension          178

   16.1.6.5 Preexisting secondary hypertension          179

  16.1.7 Blood pressure during puerperium          180

  16.1.8 Postpartum hypertension and breastfeeding          181

  16.1.9 Risk of recurrence of hypertensive disorders in a subsequent pregnancy          181

  16.1.10 Long-term cardiovascular consequences of hypertensive disorders in pregnancy          181

 16.2 Hypertensive urgencies and emergencies          183

   16.2.1 Definitions of hypertensive urgencies and emergencies          183

   16.2.2 Hospital work-up, treatments and follow-up          185

   16.2.3 Blood pressure in the emergency department          189

  16.3 Perioperative hypertension and its management          190

 17. HYPERTENSION IN ESTABLISHED CARDIOVASCULAR DISORDERS          192

  17.1 Coronary artery disease          192

   17.1.2 Treatment of hypertensive patients with coronary artery disease          193

  17.2 Heart failure          195

   17.2.1 Prevention of heart failure in hypertension          195

   17.2.2 Heart failure with reduced ejection fraction          197

   17.2.3 Heart failure with preserved ejection fraction          199

   17.2.4 Overall management of heart failure and classification          200

  17.3 Hypertension and atrial fibrillation          201

   17.3.1 Blood pressure measurement in atrial fibrillation          201

   17.3.2 Detection of atrial fibrillation          202

   17.3.3 Prevention and treatment of atrial fibrillation in hypertension          202

   17.3.4 Oral anticoagulation and BP control          204

  17.4 Valvular heart disease          206

   17.4.1 Aortic stenosis          206

   17.4.2 Aortic regurgitation          207

   17.4.3 Mitral regurgitation          207

  17.5 Cerebrovascular disease and cognition          208

   17.5.1 Management of elevated BP in acute stroke          208

    17.5.1.1 Acute hemorrhagic stroke          208

    17.5.1.2 Acute ischemic stroke          209

   17.5.2 Management of elevated BP in patients with previous stroke or transient ischemic attack          210

   17.5.3 Management of patients with cognitive dysfunction and dementia          211

  17.6 Vascular disease          213

   17.6.1 Lower extremity arterial disease          213

   17.6.2 Aortic dilatation, aneurysm and dissection          214

 18. HYPERTENSION AND DIABETES MELLITUS          215

  18.1. Epidemiology and risk classification          215

  18.2 Benefits of BP-lowering          216

  18.3 Antihypertensive drug treatment          217

 19. HYPERTENSION AND THE KIDNEY          219

  19.1 Treatment of hypertension in CKD          219

   19.1.1 Treatment BP targets          220

   19.1.2 Antihypertensive drug treatment          222

   19.1.3 Special therapeutic challenges          223

   19.1.4 Use of additional drugs for cardiovascular and nephroprotection in CKD          224

  19.2 Renovascular disease          227

  19.3 Hypertension in patients with kidney transplantation          228

 20. HYPERTENSION AND OTHER SELECTED COMORBIDITIES          231

  20.1 Obesity          231

   20.1.1 Antihypertensive pharmacotherapy in obesity          231

   20.1.2 Role of nonpharmacological weight loss intervention          232

   20.1.3 Role of weight loss medications          233

   20.1.4 Role of bariatric surgery          234

  20.2 Obstructive sleep apnea          235

  20.3 Asthma          236

  20.4 Obstructive pulmonary disease          237

  20.5 Gout and uric acid          238

  20.6 Immune-mediated inflammatory diseases          238

   20.6.1 Rheumatoid arthritis          239

   20.6.2 Psoriasic arthritis          239

   20.6.3 Systemic lupus erythematosus          240

  20.7 Glaucoma in hypertension          240

  20.8 Hypertension oncology          242

   20.8.1 Hypertension and its association with cancer          242

   20.8.2 Hypertension induced by cancer treatments          243

    20.8.2.1 Hypertension induced by VEGF inhibitors          243

    20.8.2.2 Hypertension induced by other anticancer drugs          244

    20.8.2.3 Hypertension induced by adjunctive therapies, radiotherapy or surgery          245

   20.8.3 Management of hypertension in cancer patients          245

    20.8.3.1 BP monitoring and general management before start of cancer treatment          245

    20.8.3.2 General BP-lowering therapy and management during cancer therapy          247

    20.8.3.3 Treatment of hypertension induced by VEGF inhbitors          248

   20.8.4 Follow-up and management of hypertension in cancer survivors          250

  20.9 COVID-19 and hypertension          250

   20.9.1 COVID-19 and RAS inhibitors          251

   20.9.2 COVID-19 lockdown and hypertension management          252

   20.9.3 Vaccination against SARS-CoV-2 and hypertension          252

   20.9.4 Long COVID-19 and hypertension          253

 21. FOLLOW-UP          253

  21.1 Importance of follow-up          253

  21.2 Adherence          255

   21.2.1 Definitions          255

   21.2.2 Prevalence of nonadherence and associated burden          255

   21.2.3 Methods to detect nonadherence to antihypertensive treatment          256

   21.2.4 Etiology of nonadherence to antihypertensive treatment          257

   21.2.5 When and how to screen for nonadherence          257

   21.2.6 Management of nonadherence to antihypertensive treatment          258

  21.3 Clinical inertia          259

  21.4 Patient empowerment          261

  21.5 Follow-up of low-risk hypertensive patients and deprescribing          262

  21.6 Use of telemedicine and tele-health technologies          262

  21.7 Challenges of long-term follow-up          263

  21.8 Role of general physician, pharmacies and team-based care          263

  21.9 Hypertension clinics          265

  21.10 Health risks at workplace          265

  21.11 Patient organizations          266

 22. GAPS IN EVIDENCE AND FUTURE OPPORTUNITIES          268

 23. REFERENCES          270

INTRODUCTION

The year 2023 marks the 20th anniversary of the hypertension guidelines of the European Society of Hypertension (ESH), which were published for the first time in 2003, following a proposal by Professor Alberto Zanchetti (Fig. 1). Professor Zanchetti thought that it was time for Europe to express its view on diagnostic and treatment aspects of this crucially important medical condition rather than referring, as in the past, to guidelines issued by the WHO, with or without the ISH or the scientific societies in the USA. He played a fundamental role in these first guidelines [1] as coordinator of the Writing Committee appointed by the ESH, and this was rewarded by an unexpected large success, which made these guidelines the fifth most widely quoted paper in the world across all research areas and the most quoted in the medical area. ESH offered to share these hypertension guidelines with the European Society of Cardiology (ESC), which accepted after the manuscript had already been completed, without sharing its publication in the ESC Society Journal. Subsequently, the ESH and the ESC enjoyed an equal collaboration, resulting in three further successful and also widely quoted guidelines in 2007 [2], 2013 [3] and 2018 [4] that were published in the official journals of the two Societies, except for a 2009 reappraisal of the 2007 guidelines, which was prompted by new evidence in the hypertension area and prepared only by the ESH [5].

FIGURE 1:

Alberto Zanchetti.

These 2023 hypertension guidelines have also been prepared only by the ESH because the ESC did not want to continue the previous understanding with ESH to generate “Joint Guidelines” with the equalparticipation of ESH and ESC. The rules of these guidelines, however, are largely, although not entirely, the same as those that were followed in the previous guidelines. That is, in the 2023 guidelines: (i) the members of the Task Force have been appointed by the ESH, based on recognized scientific and clinical expertise in one or more areas covered by the guidelines as well as on the documented absence of relevant conflicts of interest; (ii) selected members were initially asked to write a section or sections of the guidelines related to her or his main scientific expertise, and a small Steering Committee was appointed to harmonize the material received; (iii) multiple revisions of the text were made by back and forth interactions between the Task Force members, with a final collective critical review of the text and (iv) the final manuscript has been sent to external reviewers and further revised according to their suggestions and criticism. Particular attention has been given to the scoring of the strength of the diagnostic and treatment recommendations, which have been graded according to criteria partly different from those used in previous guidelines, i.e. with consideration for the study design but also for the quality of the collected data (see Section 1). Because of the questionable scientific value of voting, disagreements on treatment recommendations have not been resolved that way but by consensus on a shared text. Conflicting evidence or interpretation of the data have been openly admitted.

The similarity of the present and past guidelines extends to the scientific principles on which the guidelines have been based. The 2023 guidelines have been developed after careful search for new studies in the hypertension and related areas. Furthermore, as in the past, RCTs have been assigned a top value while also mentioning their limits when appropriate. However, all other relevant sources of knowledge (from observational studies down to clinical cases) have been considered, and even mechanistic studies have not been ignored, given their relevance for diagnostic and treatment decisions in individual patients. Particular attention has been given to real-world studies, which play a growing role in hypertension research and provide knowledge in areas that cannot be addressed by RCTs. Like the previous guidelines, the 2023 guidelines (i) regard their value as educational, which explains why the text addresses the data justifying the recommendations and (ii) emphasize that their recommendations are not invariably prescriptive for individual patients because they are based on average data and address conditions or diseases in general. In individual patients, the most appropriate diagnostic and treatment decisions may differ from those expressed by the guidelines.

The 2023 guidelines (i) contain several conceptual elements of novelty originated by research performed after the 2018 guidelines; (ii) deal more in depth with topics that were only briefly considered in the past and (iii) extend to several conditions that were previously unaddressed by guidelines, although frequently coexisting with hypertension and leading to specific needs for medical management. Although mainly referring to hypertension in adults, they include for the first time essential recommendations on hypertension in children, adolescents and the transition to young hypertensive adult individuals; and (iv) include a detailed index of sections and subsections focused on specific issues that has been prepared to facilitate reading of these various and multiple aspects. Furthermore, while the text addresses the sometimes nonunivocal evidence provided by research on a given issue, each section offers, as is now usual for many guidelines, a simple final list of key statements and recommendations that translate research achievements into practical use. We hope that this structure will make the ESH guidelines useful not only to the practicing physicians but also to hypertension experts and investigators.

WHAT IS NEW AND WHAT HAS CHANGED IN THE 2023 EUROPEAN SOCIETY OF HYPERTENSION ARTERIAL HYPERTENSION GUIDELINES? 1. Modified and simplified criteria for evidence grading recommendations 2. Pathophysiological background of primary hypertension 3. Clinical BP measurements by different methods and in different settings and clinical conditions 4. Thorough description of office, ambulatory and home BP measurements and value in different demographic and clinical conditions 5. Upgrading of out-of-office BP measurements in hypertension management 6. New HMOD measurements and their clinical value in hypertension work-up 7. New CV risk factors and update on CV risk assessment 8. Update and comprehensive summary of secondary forms of hypertension 9. Update on lifestyle interventions 10. Update on threshold and targets for antihypertensive drug treatment, including their possible heterogeneity in demographic and clinical subgroups of patients 11. Confirmation of preferred use of RAS blockers, CCBs and Thiazide/Thiazide-like diuretics, and their various combinations for BP-lowering treatment. Inclusion of BBs among the major antihypertensive drugs 12. Update on available combination-based drug treatment strategies, including the quadpill and the polypill 13. Emphasis and update on the diagnosis and management of true resistant hypertension 14. Update on use and position of renal denervation for antihypertensive treatment 15. Impact of hypertension and its treatment on cognitive dysfunction and dementia 16. Management of hypertension in older people according to the frailty and functional level 17. Update on treatment of hypertension in HFrEF and HFpEF 18. New diagnostic approaches to diagnosis and treatment in hypertensive patients with AF 19. Update on treatment in CKD, including kidney transplantation 20. Update and novel treatment approaches to patients with type 2 diabetes 21. Epidemiology, diagnosis and treatment in different BP phenotypes 22. Diagnosis, treatment and follow-up of hypertension in demographic and clinical conditions not or only marginally addressed in previous guidelines: a. Children/adolescents and transition to adulthood b. Young patients c. Sex-related differences d. Pregnancy and puerperium e. Peripheral artery disease f. Aortic aneurism g. Valvular heart disease h. Treatment of hypertension in acute cerebrovascular diseases i. Hypertensive emergencies/urgencies j. Perioperative hypertension k. Obesity l. COVID-19 m. Chronic inflammatory diseases n. Hypertension in oncology o. Baroreflex failure and dysautonomia p. Glaucoma 23. Detailed recommendations on patients’ follow-up strategies, including assessment and minimization of nonadher-ence and clinical inertia. 24. Mention of new potential approaches to the treatment of hypertension and containment of hypertension-related workload (tele-health, team-based treatment, role of pharmacists) 1. METHODOLOGY AND DEFINITION OF EVIDENCE 1.1 Methodology of evidence grading

The 2023 ESH guidelines aim to summarize the best available evidence for all aspects of hypertension management. The guidelines were developed by a Task Force of 59 experts form European countries, representing the areas of internal medicine, cardiology, nephrology, endocrinology, general medicine, geriatrics, pharmacology and epidemiology. Each topic was assigned to a small group of Task Force members responsible for reviewing and summarizing the available evidence within that topic. The ‘class of recommendation’ (CoR) and ‘level of evidence’ (LoE) for all recommendations were reviewed by an Evidence Grading Committee to make sure that they complied with the predefined criteria outlined in the following. Draft versions were reviewed by the Steering Committee, Task Force members and external reviewers. The final version was approved by all Task Force members.

In accordance with previous versions of the ESH guidelines, a similar system separating CoR and LoE was applied [3,4]. CoR indicates how strong a recommendation is, considering the assumed benefit versus risks and costs on a scale from I to III. Recommendation classes I and III each convey a clear message, namely a general consensus that a measure is either useful (CoR I) or not useful or even harmful (CoR III). If there is no general consensus or only doubtful evidence, an optional recommendation is conveyed with CoR II. In contrast to previous guidelines [3,4], the Task Force finds that a further subdivision of the CoR II into two subclasses (IIa and IIb) adds little value and, for the sake of simplification is no longer used. The LoE indicates how reliable the evidence underlying each recommendation is on a scale from A to C (Fig. 2). Importantly, the CoR and LoE are independent of each other, e.g. strong recommendations may build on weak evidence if the assumed benefit of an intervention or a diagnostic procedure greatly outweighs the potential risks.

FIGURE 2:

Class of recommendation (CoR) and level of evidence (LoE). BP, blood pressure, CVD, cardiovascular disease, HMOD, hypertension mediated organ damage, RCT, randomized controlled trial. aLimitations affecting the level of evidence include (but may not be limited to) high risk of bias, inability to account for important confounding factors in observational studies, questionable external validity and uncertain effect estimates (confidence intervals including negligible effect).

1.2 Level of evidence

The 2023 ESH guidelines employ the same terminology as in the 2018 ESC/ESH guidelines but with updated criteria for assessing the LoE. This revision was influenced primarily by the recommendations from the GRADE working group [6,7], but also by the most recent evidence definition used by the AHA/ACC [7].

The most important difference compared with the previous guidelines is the priority given to patient-important CV outcomes, such as stroke, MI, HF, ESKD and CV or total mortality, acknowledging that the primary aim of antihypertensive treatment is to reduce the risk of clinical outcomes and not only BP. Although BP reduction is strongly associated with a reduction in clinical events, interventions affecting BP may also affect other physiological systems with beneficial or harmful effects, and the benefit/harm ratio cannot be firmly established without clinical outcome trials.

Furthermore, risk of bias and statistical precision were considered when assigning the LoE. This means that recom-mendations supported by well conducted RCTs with CV outcomes were assigned LoE A, whereas recommendations supported by trials with a similar design and with similar outcomes, were downgraded to LoE B or C if the risk of bias was judged as high, or if effect estimates were imprecise. Meta-analyses may contribute to any level of evidence depending on the type of studies included and the quality of the meta-analysis itself [8].

For diagnostic tests and procedures, we have adopted the strategy recommended by the GRADE working group, assessing the evidence for benefit on patient-important outcomes [9]. Many diagnostic procedures rely on studies of accuracy rather than effect on outcomes, and recommendations building on such evidence is generally downgraded for indirectness even if the studies themselves are without important limitations.

2. PRINCIPLES OF HYPERTENSION PATHOPHYSIOLOGY

Hypertension is divided into a primary (formerly and still also currently referred to as ‘essential’) and secondary forms. Secondary hypertension originates from specific causes and can be detected in only a small fraction of hypertensive patients (see Section 6). Primary hypertension covers the remaining large fraction of the hypertensive population, and its origin depends on the complex interaction between a genetic background, a large number of environmental factors [10–12] and the aging process. Both genetic and environmental factors operate through alterations of CV regulatory systems, leading to an increase of systemic vascular resistance, which is the hallmark hemodynamic abnormality responsible for BP elevation in almost all hypertensive patients [13]. In the last few years, important new evidence has been obtained on the genetic background of hypertension, with more than 1000 genetic factors being identified [11,12] together with, in some instances, the biochemical and pathophysiological paths they work through [14]. New environmental factors (e.g. air pollution and noise) have been added to those already documented by older research [15–17]. Furthermore, new experimental and clinical studies have confirmed that alterations of several major CV control systems may contribute to chronic BP elevation. As shown in Fig. 3, primary hypertension may be accompanied by alterations of the RAAS, central and peripheral autonomic cardiac and vascular regulation, the endothelin system and other systems controlling vascular function, including nitric oxide and natriuretic peptides [13,18–22]. More recently, pressogenic effects (increased sodium sensitivity) of gut microbial dysbiosis have also been reported [23,24]. In addition, the immune system is likely to play a pathophysiologic role, with effects that are possibly primarily mediated by inflammation, and involve not only BP regulation (and thus development of hypertension) but also the initiation and progression of HMOD [25,26]. There is extensive experimental and clinical evidence that hypertension is associated with inflammation and immune cell activation, two processes that are driven in large part by oxidative stress. Immune cell activation is characterized by excessive production of reactive oxygen species and an altered oxidation– reduction (redox) state [26], and there is evidence that generation of reactive oxygen species is influenced by factors involved in BP regulation, such as Ang II, endothelin-1 (ET-1), aldosterone and salt (sodium) [26]. Furthermore, evidence is also available that alterations of immunoinflammation is promoted by the above-mentioned hypertension promoters such as genetic susceptibility, neurohumoral activation, salt influences and gut microbiome [10–13,18–22,27]. Although this complex interplay makes it impossible to know whether inflammation is causatively related to hypertension or represents a secondary effect of a chronic BP elevation, it is clear that inflammation and the dysregulated immune system are closely linked to each other and that immunoinflammation is involved in hypertension [25,26]. Indeed, the suggestion has been made that oxidative stress and increased generation of reactive oxygen species represent the common molecular basis linking immunoinflam-mation to hypertension. Alterations in metabolomic pathways, e.g. glucose and lipid metabolism, may also contribute, as exemplified by the sympathostimulating effect of insulin [13,28] and the favoring effect of sympathostimulation on insulin resistance [29]. Regardless of the mechanisms involved, a chronic BP elevation is known to modify the cardiac (e.g. LVH), large artery (increase in collagen and stiffening of the arterial wall) and small artery (increase in wall-to-lumen ratio) structure, which in a later hypertension phase promote the BP increase on a nonspecific anatomical basis [13]. This confirms and expands the former mosaic theory on the pathogenesis of primary hypertension as a multifactorial phenotype, which was already formulated by Page [30] in the pioneer phase of hypertension research more than 70 years ago. To the original theory, modern research has added not only new mechanisms but also, as shown in Fig. 3, strong evidence for the existence of reciprocal influences between different CV control systems, as a result of which alteration of one system may favor or reinforce alterations of the other systems and vice versa [31]. At a practical level, this multimechanistic interactive pathophysiology implies that diagnostic attempts to identify a single responsible mechanism for primary hypertension can often be not only methodologi-cally difficult but also futile. It also explains why an elevated BP can be lowered by drugs with different mechanisms of action as well as why a combination of mechanistically different drugs lowers BP much more effectively than monotherapy.

FIGURE 3:

Mechanisms involved in BP regulation and the pathophysiology of hypertension.

3. DEFINITION OF HYPERTENSION AND BP CLASSIFICATION 3.1 Definition of hypertension

According to the previous 2018 European and current international guidelines [32–34], hypertension is defined based on repeated office SBP values 140 mmHg and/or DBP 90 mmHg. However, there is a continuous relationship between BP and CV or renal morbid or fatal events starting from an office SBP >115 mmHg and a DBP >75 mmHg [35]. Therefore, this definition is arbitrary and has mainly the pragmatic purpose of simplifying the diagnosis and decision on hypertension management. In this context, the above office threshold BP values correspond to the level of BP at which the benefits of intervention (lifestyle interventions or drug treatment) exceed those of inaction, as shown by outcome-based RCTs. Based on available evidence [36] the definition of hypertension remains unchanged from the previous guidelines [4].

3.2 Classification of hypertension

The classification of office BP and definition of hypertension grades also remain the same from previous guidelines (Table 1).

TABLE 1 - Classification of office BP and definitions of hypertension grades Category Systolic (mmHg) Diastolic (mmHg) Optimal <120 and <80 Normal 120–129 and 80–84 High-normal 130–139 and/or 85–89 Grade 1 hypertension 140–159 and/or 90–99 Grade 2 hypertension 160–179 and/or 100–109 Grade 3 hypertension ≥180 and/or ≥110 Isolated systolic hypertensiona ≥140 and <90 Isolated diastolic hypertensiona <140