【医脉通】2021+SIIA共识文件：睡眠障碍、高血压和心血管疾病的诊断和治疗方法(英文版）pdf

Vol.:(0123456789)High Blood Pressure&Cardiovascular Prevention https:/doi.org/10.1007/s40292-021-00436-yCONSENSUS DOCUMENTDiagnostic andTherapeutic Approach toSleep Disorders,High Blood Pressure andCardiovascular Diseases:AConsensus Document bytheItalian Society ofHypertension(SIIA)RitaDelPinto1 GuidoGrassi2 ClaudioFerri2 MartinoF.Pengo3 CarolinaLombardi3 GiacomoPucci4 MassimoSalvetti5 GianfrancoParati3 on behalf of the Italian Society of Hypertension(SIIA)SIIA Young Researchers Study Group President of SIIA Past President of SIIA Italian Society of Hypertension(SIIA)Received:28 December 2020/Accepted:6 February 2021 The Author(s)2021AbstractHypertension is a major contributor to fatal/nonfatal cardiovascular diseases,and timely identification and appropriate man-agement of factors affecting hypertension and its control are mandatory public health issues.By inducing neurohormonal alterations and metabolic impairment,sleep disorders have an impact on a variety of cardiovascular risk factors,including hypertension,and ultimately increase the risk of cardiovascular events.There is evidence that qualitative and quantitative sleep disorders are associated with resistant hypertension and with impaired circadian blood pressure variations.However,sleep disturbances are often unrecognized,or heterogeneity exists in their management by non-specialists in the field.This document by the Italian Society of Hypertension summarizes the updated evidence linking sleep disorders to hyperten-sion and cardiovascular diseases,the major underlying mechanisms,and the possible management strategies.A simpli-fied,evidence-based diagnostic and therapeutic algorithm for comorbid hypertension and common sleep disorders,namely obstructive sleep apnoea and insomnia,is proposed.Keywords Sleep disorders Blood pressure Hypertension Cardiovascular risk1 IntroductionA proper sleep-wake cycle markedly influences a multi-tude of neuroendocrine systems,all of which are deeply involved in cardiovascular and metabolic homeostasis 1.Accordingly,qualitative and/or quantitative sleep disorders adversely affect the physiology of the hypothalamicpitui-taryadrenal axis,the glycolipid metabolism and the cardio-vascular system,thus exerting a considerable impact on the overall cardiometabolic risk 2.Specifically,observational studies and experimental evi-dence fully support the existence of a close link between sleep disorders and arterial hypertension,cardiovascular disease,diabetes mellitus and/or obesity 3.Because of the burden that all these diseases represent for the national health system,the risks of workplace accidents and traffic collisions and,finally,the losses due to reduced productiv-ity,sleep disorders and excessive daytime sleepiness exert a relevant economic and social impact that fully justifies their inclusion among public health issues.In this context,adequate knowledge of sleep disorders and related solutions The members of the SIIA Young Researchers Study Group,President of SIIA,Past President of SIIA,Italian Society of Hypertension(SIIA)listed in acknowledgement section.*Guido Grassi guido.grassiunimib.it1 Division ofInternal Medicine andNephrology,Department ofLife,Health andEnvironmental Sciences(MeSVA),Center forHypertension andCardiovascular Prevention,University ofLAquila,San Salvatore Hospital,LAquila,Italy2 Department ofMedicine andSurgery,Milano Bicocca University,San Gerardo dei Tintori Hospital,Milan,Monza,Italy3 Department ofMedicine andSurgery,San Luca Hospital Scientific Institute,Institute forResearch,Hospitalisation andHealthcare(IRCCS)Istituto Auxologico Italiano,Milano Bicocca University,Milan,Italy4 Internal Medicine Division,Department ofMedicine,University ofPerugia,“Santa Maria”Hospital,Terni,Italy5 Department ofClinical andExperimental Sciences,University ofBrescia andGeneral Medical Division 2,ASST Spedali Civili Hospital,University ofBrescia,Brescia,Italy R.Del Pinto et al.is essential for the clinician involved in the prevention and treatment of cardiovascular and metabolic diseases.Among sleep disorders affecting blood pressure(BP),obstructive sleep apnoea(OSA)has been consistently asso-ciated with increased risk of incident hypertension and treatment-resistant hypertension,as well as impaired noc-turnal physiological BP reduction(“dipping”),and is now recognised as one of the modifiable aggravating factors of the global cardiovascular risk 4.In fact,OSA events are accompanied by acute changes in cardiovascular parameters,such as large fluctuations in BP and heart rate,associated with long-term changes in fluid homeostasis,all of which increase the risk of fatal and non-fatal cardiovascular events 5.Delaying sleep onset also increases the likelihood of hypertension,with an estimated risk of 300%(odds ratio 3.27;95%confidence interval 1.208.96).In women,sleep deprivation might represent a peculiar cause of vulnerability to hypertension and cardiovascular events 6,7.In addition,the expression of more than 700 genes involved in multiple functions,including metabolic control and redox status,is modified by sleep deprivation 4,8.In parallel,a U-shaped association between sleep duration and all-cause mortality as well as increased cardiovascular risk has been described 911.On these bases,hypertension guidelines emphasise the importance of investigating the possible presence of sleep disorders in patients with resistant arterial hypertension and loss of physiological nocturnal BP dipping,as well as the need for a multidimensional approach of the problem that includes both lifestyle changes(diet,exercise,weight loss)and medications 4.He triad of“correct and timely diagnosis”“lifestyle changes”“resetting of the correct sleep-wake cycle”is gradually becoming the pillar of a correct approach to the issue of sleep disorders in cardiovascular prevention.Thus,accurately collecting a history of possible sleep disorders is essential in the evaluation of the patient with hyperten-sion and/or increased cardiovascular and/or metabolic risk 4.Lifestyle interventions,including diet and exercise,are especially relevant when excess weight is believed to favour a disordered sleep 1215.Restoring the correct function of the melatonin systeme.g.through oral administration of prolonged release melatonin at adequate dosagesmight contribute to sleep restoration and cardiometabolic protec-tion.Melatonin,in fact,is a hormone whose low levels have been frequently associated with the development of arterial hypertension 16,and whose administration in insomnia is also indicated in adults with cardiovascular comorbidities 17.The document that follows this brief premise is promoted by the Italian Society of Hypertension in order to provide a summary of the state of the art of cardiovascular and meta-bolic implications of sleep disorders.The purpose of the document is to generate an updated and shared training and information tool,with the aim of standardising the approach of clinicians to the problem and optimising the multidimen-sional management of the hypertensive patient.2 Physiology andPathology ofSleepAs Heraclitus of Ephesus wrote:“To those who are awake,there is one world in common,but of those who are asleep,each is withdrawn to a private world of his own.”,implying that the concept of sleep is an active process and is unique to each individual.Sleep is one of the most important behav-ioural characteristics of humans and animals,which forces them to spend a significant proportion of life in a state where reactions to environmental stimuli are inhibited and during which important cognitive processes are developed.Although there are still many aspects to be defined,in particular concerning the meaning and function of sleep,research in the neurophysiology field over the last 30 years has made it possible to clarify some fundamental concepts such as the sleep-wake cycle and circadian rhythms.As anticipated,sleep is a reversible state of interruption of motor interactions with the environment and is present in many animal species,even in simple organisms such as yeast.It is divided into rapid eye movement(REM)sleep,contrasted with non-REM sleep,where this oculographic feature does not occur.This descriptive definition is associated with the pres-ence/absence of a series of physiological functions that char-acterise REM and non-REM sleep.In the former,in addition to the known eye movements,there is a marked muscular atony of the antigravity muscles which spares the diaphragm.Non-REM sleep,which accounts for about 80%of total sleep time,is further divided into 4 categories,according to the first classification by Rechtschaffen and Kales,reduced to 3(N1,N2 and N3)in 2007 after a re-evaluation by the Ameri-can Academy of Sleep Medicine 18,19.During non-REM sleep,the brain works in a low-consumption mode that is visible at the electroencephalographic level through slow and broad waves;heart rate,respiratory rate and BP decrease in absolute values and become less variable.The alternation of REM and non-REM sleep occurs sev-eral times(on average 45)during the night at intervals of about 90120 min.Stage N3 of non-REM sleep is more prominent in the first part of sleep,while REM sleep is more pronounced in the second part.The alternation of sleeping and waking is part of a more complex process called a circadian rhythm.The circadian rhythm is a broader concept that is defined with a fundamen-tal characteristic:it is an endogenous process that can occur even independently from the variation of the environmental features.However,at the same time,it is a process that is able to adapt to environmental stimuli while maintaining its own periodicity.The ability of a cell or complex organism to keep track of time is inherent in a series of molecular mechanisms,the discovery of which earned Jeffrey C.Hall,Michael Rosbash and Michael W.Young the Nobel Prize in 2017 thanks to a series of studies on Drosophila melanogaster.The presence of such molecular mechanisms that can establish the circadian rhythm universally in the differ-ent cells and tissues of an organism poses a risk of lack of synchronisation.This risk is minimised by the presence of a hierarchi-cal organisation of cells capable of maintaining a circadian rhythm,at the top of which is the suprachiasmatic nucleus(SCN)in the hypothalamus.The SCN is located in a strate-gic area which is near the optic chiasm.In this way it can receive optical stimuli from one of the most important external factors(Zeitgeber,from the Ger-man,“time giver”),able to synchronise a biological clock,i.e.light.The extraordinary ability of the SCN to coordinate the biological clock of an organism has been confirmed in experiments where,by dispersing the single SCN neurons in culture,the molecular rhythms of each neuron were observed which,however,were out of step with one another 20.In the intact SCN nucleus,on the other hand,a precise coordination of the various neurons is observed through the synaptic terminations,which use various neurotransmitters,including gamma-aminobutyric acid(GABA),allowing a common and synchronised output.The activity of the SCN nucleus characterises a wide vari-ety of cells and tissues of our body,starting from the para-ventricular nucleus(PVN)of the hypothalamus on which it exerts an inhibitory action by conditioning the activity of the endocrine system and the autonomic nervous sys-tem with particular regard to the production of melatonin.Therefore,since the activity of SCN is dependent on light stimuli,an increase in SCN activity during exposure to light is effectively able to reduce the production of melatonin by the pineal gland 21.Melatonin is a fundamental neurohormone for the syn-chronisation of the biological clock.It is produced by the pineal gland during the night hours reaching maximum con-centrations in the blood between 2:00 a.m.and 4:00 a.m.and then gradually decreasing as the morning approaches.Neurones located in the brain stem are also involved in the circadian regulation of sympathetic and vagal activ-ity and the relative modulation by the autonomic nervous system of the cardiovascular system between day and night 22.Sleep disorders can be grouped according to different classifications,one of the most widely used is the Interna-tional Classification of Sleep Disorders(ICSD),which is now in its third edition and produced by the American Acad-emy of Sleep Medicine 23.This classification divides sleep disorders into the fol-lowing categories:1)Insomnia2)Sleep-related breathing disorders3)Central disorders of hypersomnolence4)Circadian rhythm sleep-wake disorders5)Parasomnias6)Sleep-related movement disorders.The first group includes insomnia,which is defined as a disorder characterised by difficulty in falling asleep or stay-ing asleep,or by nonrestorative sleep.This disorder affects the subjective feeling of well-being,even causing daytime psychic,cognitive and somatic alterations.This is the most frequently reported sleep disorder in clinical practice and in the general population.It is fre-quently associated with other disorders;in particular,the most well-known and described link in the scientific litera-ture is undoubtedly with mental disorders.In particular,it has been shown that the presence of insomnia is capable of predicting the onset of a depressive episode,anxiety,alcohol abuse,or psychosis and represents a risk for the development of suicidal ideation and behaviour 24.Insomnia is also associated with high cardiovascular mor-bidity and mortality,particularly when accompanied by a short sleep duration(Fig.1)25.One possible explanation of this could be the altered BP profile over 24h of sleepless patients with reduced dipping and nocturnal hypertension 26.The second group encompasses all respiratory disor-ders that occur during sleep,the most prevalent being OSA syndrome(OSAS).OSAS is determined by a transient but repeated interruption of breathing during sleep.This phe-nomenon causes a qualitative change in night-time rest,which may lead to symptoms during waking,such as exces-sive daytime sleepiness and fatigue.As previously seen,sleep induces a state of general mus-cle relaxation,particularly in the REM stage.The loss of muscle tone can cause the upper airway walls(hypopharynx)to narrow and begin to vibrate,thus producing the well-known snoring phenomenon.In extreme conditions,an actual collapse of the walls can occur,or even the complete airway obstruction.In this case our brain briefly interrupts sleep by awakening;this leads to the recovery of adequate muscle tone,stopping the apnoea phenomenon.Patients suf-fering from OSA,however,may not be aware of the many awakenings associated with apnoea,because sometimes wakefulness and lighter sleep are not so intense or prolonged that the individual reaches a state of consciousness.At morning awakening,however,there may often be a feeling R.Del Pinto et al.of not having had a restful nights sleep and symptoms such as excessive slee