Sindrome delle apnee notturne ipertensione arteriosa M. Scoppio Responsabile reparto di Nefrologia Ambulatorio ipertensione arteriosa Ospedale San Camillo-Forlanini 26 maggio 2007

Sleep apnea and hypertension Il 96% degli uomini e il 65% delle donne con “ipertensione resistente” hanno OSA Gli ipertesi resitenti con OSA hanno livelli più alti di aldosterone plasmatico e incidenza più elevata di aldosteronismo primario, rispetto agli ipertesi resistenti senza OSA OSA E IPERTENSIONE RESISTENTE

Sleep Apnea and Potential Health Risks Excessive sleepiness Neurocognitive deficits Crashes (motorcar accidents) Sleep Apnea Hypertension Cardiovasculare disease (IMA,stroke,SCA,CHF) Insulin-resistance

In Patients with Cardiovascular and Cerebrovascular Disease Prevalence of OSA In Patients with Cardiovascular and Cerebrovascular Disease 50% ------------ Hypertension 25% ----------- Congestive Cardiac Failure OSA 60% -------- Stroke 30% --------- Acute Coronary Syndrome Lattimore Jl JACC 2003;41

and resulting abnormal regulation breathing during sleep OSA Morbo di Alzheimer Link genetico APOE ε4 two recent reports have found increased OSA in subjects with APOE ε4, a genetic factor associated with Alzheimer’s disease. The association of APOE ε4 with OSA has been suggested to be mediated by damage to the CNS and resulting abnormal regulation breathing during sleep Am J Respir Crit Care Med Vol 170. pp 1349–1353, 2007

Obstructive sleep apnea and risk for hypertension Peppard PE. N Engl J Med. 2000; 342:1378-84

General population epidemiology studies EVIDENCE ON THE ASSOCIATION BETWEEN OSA AND HYPERTENSION: Recent Human Studies General population epidemiology studies Clinic based epidemiology studies Case control studies Intervention studies

EVIDENCE ON THE ASSOCIATION BETWEEN OSA AND HYPERTENSION: Recent Human Studies Studio trasversale Studio longitudinale

LINK OBESI OSA IPERTENSIONE 2/3 paz. con OSA ½ paz. ipertesi 2/3 paz. obesi IPERTENSIONE

OSA and Impaired Glucose Metabolism Meslier et al 2003 595 male patients referred for polysomnography underwent a 2 hour oral glucose tolerance test. 494 pts had OSAS (AHI > 10) Fasting and postload blood glucose increased with severity of sleep apnea Insulin sensitivity decreased with increasing severity of sleep apnea BMI, age and AHI are all have an independent effect on blood glucose and insulin sensitivity Ip et al 2002 185 pts with OSAS (AHI>5) Insulin resistance increased with age obesity (main determinant) Independent determinants of OSA were AHI and min 02 sat Punjabi et al 2003 [Review] Habitual snoring is associated with abnormal fasting glucose and insulin values independent of age and BMI Prospective data from two separate studies indicate that habitual snoring is associated with more than a 2-fold risk of developing DM type II over a ten year period independent of BMI and other confounders Several studies have suggested that the minimum oxygen saturation and AHI are predictive of glucose intolerance and insulin resistance independent of BMI, age and waist to hip ratio

Sindrome Metabolica: Definizione Cluster di fattori di rischio emodinamici e metabolici tradizionali e non tradizionali (emergenti), che associati aumentano il rischio di diabete tipo 2 e di eventi cardiovascolari Danno logaritmico

Definition of metabolic syndrome Central obesity Men >102 cm Women >88 cm TG ≥150 mg/dL HDL cholesterol Men <40 mg/dL Women <50 mg/dL Blood pressure ≥130/≥85mmHg Fasting glucose ≥110 mg/dL Definition of metabolic syndrome Three or more of the following five risk factors: Waist circumference

Despite therapeutic advances, cardiovascular disease remains the leading cause of death 5 10 15 20 25 30 35 Number of deaths (thousands) Male Female % of all deaths (right axis) No. of deaths (left axis) % All deaths (male + female) Despite therapeutic advances, cardiovascular disease remains the leading cause of death (USA) Survey data from the Centers for Disease Control National Center for Health Statistics in the USA illustrate the continuing burden of mortality arising from cardiovascular disease. The left hand axis shows the numbers of deaths attributed to specific conditions in men and women in 2002. The right hand axis expresses the number of deaths in men and women combined as a percentage of the total numbers of deaths during that year. Cardiovascular disease remains the leading killer, with more impact on mortality rates than other major sources of mortality, such as cancer, respiratory disease, accidents, or diabetes. National Center for Health Statistics. Health, United States, 2004 With Chartbook on Trends in the Health of Americans. Hyattsville, Maryland: 2004. Data for 2002 National Center for Health Statistics 2004

Unmet clinical needs to address in the next decade Major Unmet Clinical Need Classical Risk Factors Novel Risk Factors Metabolic syndrome Abdominal Obesity HDL-C TG TNF IL-6 PAI-1 Glu Insulin  LDL-C  BP Smoking T2DM Unmet clinical needs to address in the next decade The adverse effects of cardiovascular prognosis of the classical cardiovascular risk factors, hypercholesterolaemia, hypertension and smoking, are well understood. Our increasing understanding of the pathophysiology of cardiovascular disease is now defining the importance of a range of new cardiovascular risk factors. Among these, abdominal obesity, low HDL-C, hypertriglyceridaemia and the hyperglycaemia associated with insulin resistance are all recognised criteria for the diagnosis of the metabolic syndrome. However, a range of important novel risk factors or risk markers for cardiovascular disease are also associated with the metabolic syndrome, although not yet included within its definition. These include chronic, low-grade inflammation, and disturbances in the secretion of bioactive substances from adipocytes (‘adipokines’) that influence cardiovascular structure and function. The cardiovascular risk factors associated with the metabolic syndrome, whether included within its diagnostic criteria or not, contribute to the progression of atherosclerotic cardiometabolic disease, and represent an important clinical need inadequately addressed by current therapies. CARDIOVASCULAR DISEASE

“TWIN EPIDEMICS” OBESITA’ DIABETE TIPO 2 IPERTENSIONE MALATTIE DIABESITY GLOBESITY IPERTENSIONE ARTERIOSA MALATTIE CARDIO-VASCOLARI

Childhood Obesity, Inflammation, and Apnea What Is the Future for Our Children? numerous recent studies have demonstrated the presence of hypertension and increased inflammation in children with OSAS AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005

OSA OSA e SINDROME METABOLICA PCOS NEFROPATIA URATICA NASH Ipertensione Obesità Insulino-resistenza Dislipidemia aterogena OSA PCOS NEFROPATIA URATICA NASH L’OSA ha probabilità 9 volte superiore di sviluppare sindrome metabolica rispetto alla popolazione di controllo

Obesità (sindrome metabolica) OSA ?

GRASSO VISCERALE Valutazione del sovrappeso e dell’obesità Indice di massa corporea: Peso (kg)/altezza(m2) Circonferenza addominale Rischio elevato: Uomini > 102 cm Donne > 88 cm GRASSO VISCERALE The Practical Guide Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. NIH Publication, October 2000 NIH Pub No 00-4084

Effetti cardiometabolici sfavorevoli dei prodotti degli adipociti ↑ Lipoprotein lipasi Ipertensione ↑ IL-6 ↑ Angiotensinogeno Infiammazione ↑ Insulina Dislipidemia aterogenica ↑ FFA Adipose tissue ↑ TNFα ↑ Resistina ↑ Leptina ↑ Adipsina (Complemento D) Effetti cardiometabolici sfavorevoli dei prodotti degli adipociti Questa diapositiva mostra un quadro più completo delle sostanze bioattive prodotte dagli adipociti, che modulano l’insulino resistenza e il rischio cardiovascolare. Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology 2003;144:2195-200. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:347-55. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415-28. ↑ Lactato Diabete tipo 2 ↑ Inibitore dell’attivatore del plasminogeno-1 (PAI-1) ↓ Adiponectina Aterosclerosi Trombosi Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

ipossiemia - ipercapnia Eventi cardiovascolari Sindrome Metabolica e OSA OSA Insulino resistenza ipossiemia - ipercapnia Ag II ROS (radicali liberi) Ipertono simpatico Eventi cardiovascolari Ipertensione arteriosa

IPERTONO SIMPATICO renale

Profilo pressorio caratteristico dell’OSA Ipertensione arteriosa diastolica Ipertensione clinica Ritmo circadiano di tipo non-dipper Eccessivo rialzo pressorio al risveglio Alta variabilità pressoria (DS) Ipertensione secondaria e resistente

UTILITA’ dell’ABPM

Rilevanza clinica dei fenomeni pressori nelle 24 ore Danno d’organo Pressione notturna più alta Minore  giorno/notte Eccessivo aumento pressorio mattutino Aumento della variabilità pressoria Picchi pressori eccessivi/ numerosi Rischio cardiovascolare Progressione a nefropatia diabetica Associazione con un picco mattutino degli eventi cardiovascolari

(> 15 mmHg) o normale (< 15 mmHg) Analisi di Kaplan-Meier per gli eventi cardiovascolari fatali e non fatali in pazienti con variabilità pressoria aumentata (> 15 mmHg) o normale (< 15 mmHg) Variabilità ≤ 15 Variabilità > 15 Sander D. et al, Circulation 2000; 102: 1536-1541

Variabilità notturna della PAS Variabilità della pressione sistolica come fattore di rischio per ictus e mortalità cardiovascolare negli ipertesi anziani Rischio di ictus a 2 anni Variabilità notturna della PAS PAS notturna (mmHg) Journal of Hypertension 2003; 21: 1-7

OSA e IPERTENSIONE ARTERIOSA Monitoraggio ambulatorio della PA 24 ore e rialzo pressorio al risveglio (morning surge pressure)

Mortalità nelle prime tre ore dopo il risveglio 25 20 Numero di morti 10 sonno 0-3 3-6 6-9 9-12 12-15 Ore dopo il risveglio Willich. Am J Cardiol 1992; 70: 65-68

Variazioni circadiane nell’incidenza di morte cardiaca improvvisa - Framingham Heart Study Ore del giorno Willich. Am J Cardiol 1987; 60: 801-806

Sudden cardiac death and OSA Gami, A. S. et al. N Engl J Med 2005;352:1206-1214

Picchi temporali dei ritmi circadiani umani Cortisolo RAS AgII Aldosterone Catecolamine Adesività piastrinica Viscosità ematica PA h 6 h 18 FC h 12 NO Fibrinolisi

OSA e EPO

early clinical signs of atherosclerosis ! Elevated Levels of C-Reactive Protein and Interleukin-6 in Patients With Obstructive Sleep Apnea Syndrome Are Decreased by Nasal Continuous Positive Airway Pressure early clinical signs of atherosclerosis ! Circulation. 2003;107

Sleep-related disorder Incidence (%) Central sleep apnea 25 Incidence of sleep-related disorders in 440 consecutive patients with HF Sleep-related disorder Incidence (%) Central sleep apnea 25 Obstructive sleep apnea 28 Milder sleep-related disorders 18 No sleep-related disorder 29 Lamp B. Heart Failure Society of America 2004 Annual Scientific Meeting; September 12-15, 2004; Toronto

SO2 e Massa Ventricolare sinistra Data supporting a possible cause and effect relationship between OSA and LVH. 6 months of nocturnal CPAP to patients with severe OSA was associated with a significant reduction in LV wall thickness. Chest 2003;124 Hypertension 2007;49:34-39

Correlazione tra AHI e SS e GC JACC Vol. 47, No. 7, 2006

Effetto della CPAP su SS e GC JACC Vol. 47, No. 7, 2006

Nocturnal Ischemic Events in Patients With Obstructive Sleep Apnea Syndrome. Effects of Continuous Positive Air Pressure Treatment. CPAP 10/51 paz. con OSA J Am Coll Cardiol 1999;34

OSA treatment in CAD Milleron et al Eur Heart J 2004

Treatment of heart failure Once confirmed LV dysfunction on echo (not symptoms alone), treatment is a formula: Diuretics Spironolactone ACE inhibitor/ARBs Beta blocker And now CPAP Drug therapy alone does not decrease severity of sleep apnea in heart failure

Arrhythmias associated with SDB The following have been associated with SDB: Classically severe bradycardia (sinus arrest, AV block) Atrial and ventricular ectopics SVT, Atrial flutter, AF Sustained and nonsustained VT Causality is not proven but tend to occur most with severe OSA and hypoxia

OSA e FA Gami AS Circulation 2004;110:364-7

Recurrence of AF 12 months after cardioversion Kanagala R Circulation 2003;107:2589-94

Prevalence of OSA after stroke Harbison Good Parra Dyken Bassetti Wessendorf Davies >40%

Terapia dell'ipertensione associata ad OSA

Wolk et al. Hypertension, 2003; 42

TERAPIA ANTIPERTENSIVA SINDROME METABOLICA CONTROLLO PRESSORIO PROTEZIONE METABOLICA PROTEZIONE D’ORGANO

Terapia antipertensiva nella Sindrome Metabolica Farmaci che riducono la pressione arteriosa e che migliorano il quadro metabolico BLOCCANTI IL SRA ACE-inibitori Sartani

Proliferazione cellulare Potenziale influenza di telmisartan sui recettori PPAR e sull’Angiotensina II SARTANI + – PPAR Angiotensina II Insulino resistenza Dislipidemia Flogosi cellulare Proliferazione cellulare Ipertensione Stress ossidativo Aterosclerosi Kurtz TW et al. J Hyperten 2004; 22: 2253-2261

ANTIALDOSTERONICI treatment of aldosterone excess induces not only the improvement of the cardiac alterations, but also of the metabolic complications related to hyperaldosteronism Journal of Hypertension 2007, 25:177–186

Diuretics AT1-receptor blockers ß-blockers Calcium antagonists ACE inhibitors Calcium antagonists AT1-receptor blockers ß-blockers 1-blockers 2003 European Society of Hypertension - European Society of Cardiology guidelines for the management of arterial hypertension

Ten Years Ago - April 1993! SLEEP APNEA – A MAJOR PUBLIC HEALTH PROBLEM EDITORIAL “Among specific sleep disorders, the most serious in terms of morbidity and mortality is obstructive sleep apnea.” “... it is time for the nation to wake up to the staggering impact of sleep disturbances on the health and welfare of our society, an impact that rivals that of smoking.”

Vi ringrazio per l'ascolto M. Scoppio