1. La morte cerebrovascolare: può presentarsi come la morte improvvisa cardiaca? Giuseppe Micieli Dip Neurologia d’Urgenza IRCCS Istituto Neurologico Nazionale C Mondino Pavia Eleventh International Symposium Heart Failure & Co. Morte Improvvisa Reggia di Caserta 29-30 Aprile 2011

2. After a stroke/TIA, patients are at high risk of short-term non-fatal stroke and of long-term fatal CHD CHD is highly prevalent at autopsy in patients with stroke TIA Recent studies confirm 10-year incidence of CHD in patients with stroke/TIA is 20% Secondary prevention should not only focus on the first 2-3 years Long-term (4-5 years) secondary prevention trials (PROGRESS, SPARCL) show reduction in CHD events

3. Malattia cerebrovascolare: sottotipi di ictus Albers GW et al. Chest. 1998;114:683S-698S.. Rosamond WD et al. Stroke. 1999;30:736-743. Ictus ischemico (83%)Ictus emorragico (17%) Malattia aterotrombotica (20%) Cardioembolismo (20%) Patologia lacunare dei piccoli vasi (25%) Criptogenetico e da cause rare(30%) Emorragia intracranica (59%) Emorragia subaracnoidea (41%)

4. – Mediche: Cardiocircolatorie Respiratorie Infettive Internistiche – Neurologiche: Stroke in evoluzione Infarcimento emorragico Ipertensione endocranica Crisi epilettiche Complicanze

5. Numbers and causes of death per week from stroke onset Prosser J et al, Stroke 2007;38:2295-2302

6. 4,5 hrs 16 hrs TC cerebrale: ischemia cerebrale ed edema

8. 30-day Case-Fatality Rate Stroke type No. CFR 95%CI Subarachnoid hemorrhage (n=118) 40 33.9% 25.4-42.4 Intracerebral hemorrhage (n=588) 284 48.3% 44.3-52.4 Cerebral ischemia (n=3594) 763 21.2% 19.9-22.5 Ill-defined events (n=53) 39 73.6% 61.7-85.5 Total (n=4353) 1126 25.9% 24.6-27.2 CFR: case-fatality rate, CI: confidence interval L’Aquila Stroke Registry, 2004

9. Time interval qualifying sudden death (from symptoms) Up to 1 h Lie JT et al, 1975; Herzog CA et al, 2006 Within 6 h Davies MJ et al, 1987; Corrado D et al, 1992 Up to 24 h WHO, Sarkioja T et al, 1984; Siboni A et al, 1986 The day of the dead (1923-1924) Diego Rivera

10. Unexpected natural death among Korean workers (1994-1995) Park J et al. J Occup Health 1999; 41:238-243

11. Effects of cerebral lesions on the heart and blood pressure Effects of cerebral lesions on the heart and blood pressure Modified from Norris, 1983

13. 64-year-old woman collapsed in the lobby of her apartment building CT-scan: right subdural hematoma with intracerebral right temporal and insular hemorrhage insular hemorrhage Baranchuk A et al. Cardiol J 2009;16:105-112 within 24 hours of admission within 72 hours of admission

14. Brugada syndrome revealed by vertigo caused by cerebellar infarction (36-year-old man) Denier C et al. Eur J Neurol 2010;17:e35-e36

15. Neurogenic T wave inversion in pure left stroke associated with hyperhomocysteinemia Mandrioli J et al. JNNP 2003 admission 7 days after the second stroke

16. Sudden cardiac arrest in a successfully embolized case of giant VA aneurysm with hydrocephalus Mishra NK. Sur Neurol 2007;67:652-653

17. QT variability in CADASIL Piccirillo G et al. Eur J Neurol 2008;15:1216-1221

18. Elettrocardiographic changes during central nervous system lesions Baranchuk A et al. Cardiol J 2009;16:105-112

19. Neuroanatomic basis of stroke-related myocardial injury Zhu et al, Neurology 2006

20. Stroke-induced sudden-autonomic death Role of the insular cortex in the pathophysiology of sudden death Oppenheimer et al, 1991 Significant modulating effects of ventromedial prefrontal cortex (VMPFC) on cardiovascular responses to emotional stimuli Hiltz MJ et al. 2006 Hemispheric dominance of sympathetic (RH) or parasympathetic (LH) activity Zamrini EY et al, 1990; Hiltz MJ et al, 2001

21. Left-hemispheric inactivation increased sympathetic cardiovascular modulation; right- hemispheric inactivity furthered parasympathetic activity Hitz MJ et al, 2001 Tailored resection of temporal lobe areas lowers sympathetic cardiovascular activation (shift towards cardiovagal predominance with possibile bradycardia or even asystole) Hiltz MJ et al 2006, Hiltz et al, 2001 Stroke-induced sudden-autonomic death

22. Predictors of cardiac death within 5 years after first ischemic stroke: multivariate analysis Rincon F et al. Stroke 2008;39:2425-2431

23. Infarction involving parietal lobe seem to be associated with an increased risk of cardiac events (HR 4.45 of cardiac death) Rincon et al, 2008 Similar high risk of death after right parietal lobe infarction when infarct size is considered Rincon et al, 2008 Probably, the parietal lobe has buffering effects on the insular region which are disinhibited after loss of parietal activity Stroke-induced sudden-autonomic death

24. Cardiovascular Response after Insula Stimulation in Human Subjects * significant difference compared with right anterior insula, p < 0.005 ** significant difference compared with right posterior insula, p < 0.005 # significant difference compared with aggregate of right anterior and posterior insula, p < 0.005 § significant difference compared with left posterior insula, p < 0.005 ## significant difference compared with aggregate of left anterior and posterior insula, p < 0.005 Oppenheimer et al, 1992

25. Insular vs non insular involvement Right vs Left insula Atrial fibrillation0.7720.009 Sinus tachycardia HR>120 bpm 0.0010.118 Sinus bradicardia HR<45 bpm0.8020.896 Atrioventricular block0.9690.029 Ectopic beats >10%0.0320.016 Prolonged QTc0.4700.736 ST depression0.1360.060 ST elevation0.0110.148 Inverted T wave0.1440.040 Isoform T wave0.067- ECG abnormalities and insular involvement Christensen et al, JNNP 2005 mod.

26. Two-year survival curves according to right-insular involvement Abboud H et al, Ann Neurol 2006;59:691-699

27. ECG predictors for mortality among stroke cases with insular involvement Abboud H et al, Ann Neurol 2006;59:691-699

28. Plasma norepinephrine concentration Meyer S et al. Neuroreport 2004;15:357-361

29. Plasma epinephrine concentration Meyer S et al. Neuroreport, 2004;15:357-361

30. Pathological Findings in the Heart of Patients with Brain Lesions Focal myocytolysis Myofibrillar degeneration Lipofuscin pigment deposition in myofibrils Hystocytic infiltration of the diffuse necrotic areas Greenhoot and Reichenbach, 1969

31. Contraction band necrosis (coagulative myocytolysis, myofibrillar degeneration) Fresh endocardial hemorrhage The neurocardiac lesion: 30-year-old man died during an acute psychological stress Intense mineralization within minutes of the onset of contraction band necrosis Myocardial necrosis main patterns (Baroldi F, 1975) : a)Coagulation necrosis b)Colliquative myocytolysis c)Coagulative myocytolysis (in reperfusion areas around regions of coagulation necrosis in transplanted heart, in sudden unexpected and accidental death, in hearts exposed to toxic levels of catecholamines) Samuels MA. Circulation 2007;116:77-84

32. Cascade of events that lead to neurocardiac damage Samuels MA, Circulation 2007;116:7784

33. Possible therapeutic approaches aimed to prevent neurocardiac damage Samuels MA, Circulation 2007;116:7784