1. A Transition From Disease to Health
2. Heart – Brain Integration
3. Imaging / Omics / Regeneration / Life Style
Complex CAD (5) PVD-P
Valv. – CM AF
Sub-Clinical Arterial (2) DBD/Frailty (4)
Health Political (1) Personal (3)
1980 1990 2000 2010 2015
1990 2000 2010 2015 2020
Projected US Population Demographics by Age / Sex
2010, 2030, and 2050
JC Kovacic, EG Nabel, V Fuster et.al. Circ. 2011;123:1650 US Census Bureau
In 2030, nearly 1 in 5 US residents is expected to by > 65 years.
By 2050, this age group is projected to more than double
2010
2030
2050
Projected Number of Americans 65 Years of
Age or Older with Alzheimer’s Disease
S Okie NEJM. 2011;365:1069
1. A Transition From Disease to Health
2. Heart – Brain Integration
3. Imaging / Omics / Regeneration / Life Style
Complex CAD (5) PVD-P
Valv. – CM AF
Sub-Clinical Arterial (2) DBD/Frailty (1/4)
Health Political (1) Personal (3)
1980 1990 2000 2010 2015
1990 2000 2010 2015 2020
1). Risk Factors of CV Disease
White Matter & Lacunar Lesions (DBD)
JC Kovacic, V Fuster et. al. Circulation. 2011;123:1900
MA Lim et. al. Clin Geriatr Med. 2009;25:191.
CT Loy et. al. Lancet 2014; 383: 828 (Australia)
DBD / AD - Mendelian vs Acquired
25% >65y – FH Dementia, 20% Dementia
DBD/AD - CVRFs, Lacunar Les., < Cognitive
MRI – Perfusion
1.V Novak, I Hajjar. Nat. Rev. Cardiol. 2010;7:686(HMS)2. HW Querfurth, FM LaFerla. NEJM 2010; 362:329
Ischemia affects 60 to 90% of patients with Alzheimer’s – RFs ?3. WB White et al.Circ 2011;124:2312 (Farmington,Yale) 4. AHA/ASA, Stroke 2011; 42:26725. WHO - Dementia report 20126. JB Toledo et al. Brain July 10, 2013 – Autopsy (n=6000)7. C Russo, RL Sacco et.al. Circ. 2013;128:1105 8. CARDIA (K Yaffe et al) Circ. 2015; 129 (In Press)9. JI Friedman, ZA Fayad, J Narula, V Fuster - 2015(In Press)10. AM Rawlings et al., Ann Intern Med 2014; 161:78511. N Mattsson et al. Brain 2014;137:150
ALZHEIMER’S - VASCULAR COMPONENT - RFs ?
JC Kovacic, V Fuster et. al. Circulation. 2011;123:1900
MA Lim et. al. Clin Geriatr Med. 2009;25:191.
DBD/AD - CVRFs, Lacunar Les., < Cognitive
MRI – Perfusion
1.V Novak, I Hajjar. Nat. Rev. Cardiol. 2010;7:686(HMS)2. HW Querfurth, FM LaFerla. NEJM 2010; 362:329
Ischemia affects 60 to 90% of patients with Alzheimer’s – RFs ?3. WB White et al.Circ 2011;124:2312 (Farmington,Yale) 4. AHA/ASA, Stroke 2011; 42:26725. WHO - Dementia report 20126. JB Toledo et al. Brain July 10, 2013 – Autopsy (n=6000)7. C Russo, RL Sacco et.al. Circ. 2013;128:1105 8. CARDIA (K Yaffe et al) Circ. 2014; 129 (In Press)9. JI Friedman, ZA Fayad, J Narula, V Fuster - 2015 (In Press)10. AM Rawlings et al., Ann Intern Med 2014; 161:78511. N Mattsson et al. Brain 2014;137:150
8. Early Adult to Midlife
CV Risk Factors & Cognitive Function
Studies have linked midlife and late-life CV risk factors
(CVRFs) to cognitive function, yet little is known about
CVRF exposure in early adulthood and subsequent
cognitive function. In a prospective study of 3381 adults
(age, 18-30 years at baseline) with 25 years of follow-up, we
assessed cognitive function at year 25 (2010-2011) with the
Digit Symbol Substitution Test, Stroop Test, and Rey
Auditory Verbal Learning Test. Cumulative exposure to
CVRFs from early to middle adulthood was associated with
worse cognition in midlife.
CARDIA (K Yaffe, et al.) Circulation 2015; 129 (In Press) – 4 Cities
Early Adult to Midlife (N=3381, FU 25 yrs)
CV Risk Factors and Cognitive Function
8. CARDIA (K Yaffe, et al.) Circ 2015 (Birmingham, Chicago, Minneapolis, Oakland)
9.JI Friedman, ZA Fayad, J Narula, V Fuster - 2015 (In Press) – MRI: WMH, BF – BP, Diabetes
Adjusted For Age, Sex, Race And Education
10. Diabetes in Midlife and Cognitive Change
Objective: To determine whether diabetes in midlife is
associated with 20-year cognitive decline and to characterize
long-term cognitive decline across clinical categories or
HBA1c levels.
Setting: Atherosclerosis Risk in Communities Study-ARIC
Participants: 13,351 black and white adults aged 48 to 67.
Results: In diabetes there was a 19% greater cognitive decline
over 20 years compared with no diabetes. Participants with
HBA1c level 7.0% had greater decline. Longer-duration
diabetes was also associated with greater late-life cognitive
decline.
AM Rawlings et al., Ann Intern Med 2014; 161:785
Cognitive Z Score Decline By Hba1c
Level Compared
with No Diabetes And Hba1c
Level <5.7%
AM Rawlings et. al. Ann Intern Med. 2014;161:785
Neuroimaging (MRI arterial and structural, PET Florbetapir) was tested in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer’s disease (n = 24). Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-b load was related to lower cerebral blood flow
11.
Circulation. 2014;130:786
TAN SNIP Projects
TRANS-ATLANTIC NETWORK TO STUDY STEPWISE NONINVASIVE
IMAGING AS A TOOL FOR CV PROGNOSIS & PREVENTION
1. A Transition From Disease to Health
2. Heart – Brain Integration
3. Imaging / Omics / Regeneration / Life Style
Complex CAD (5) PVD-P
Valv. – CM AF
Sub-Clinical Arterial (2) DBD/Frailty (2/4)
Health Political (1) Personal (3)
1980 1990 2000 2010 2015
1990 2000 2010 2015 2020
2). Silent Cerebral Infarcts
Cardiac Disease And Procedures
ME Hassell et. al. Nat. Rev. Cardiol. 2013;10:696
2a). LA Reservoir Function (3D Echo) and Volumes Are Associated With Subclinical CVD (MRI)
CABL Study (C Russo et. al.) J Am Coll Cardiol Img 2013;6:313 (US. Japan)
Normal Brain And Subclinical IschemicChanges
White Matter Hyperintensities
Cortical infarctionLacunar infarction
Prevalence of Silent Cerebral Ischemia in Paroxysmal andPersistent AF and Correlation With Cognitive Function
F Gaita et. al. J Am Coll Cardiol 2013;62:1990 (Italy)
Prevalence Of Scis In Patients With AF According To The Method Of SCI Diagnosis
S Kalantarian et. al. Ann Intern Med. 2014;161:650
Cardiac Imaging For Assessment Of Left Atrial Appendage Stasis & Thrombosis
J Romero et. al. Nat Rev Cardiol. 2014;11:470
JP Fanning et. al. Circulation. 2014;129:504
2b). Spectrum Of Neurological Injury In TAVI
JP Fanning et. al. Circulation. 2014;129:504
Thirty-day Stroke Incidence Following TAVI
JP Fanning et. al. Circulation. 2014;129:504
Silent cerebral ischemic lesionson DW-MRI post-TAVI
JP Fanning et. al. Circulation. 2014;129:504
TAVI -Transcranial Doppler Detected Embolic Load
JP Fanning et. al. Circulation. 2014;129:504
Tavi -Embolic Protection Devices
Embrella Deflector(Edwards LifeSciences,
Irvine, CA)
Montage 2 Capture Device(Claret Medical, Santa Rosa,
CA)
Triguard Cerebral Deflector
(Keystone Heart, Herzliya, Israel)
1. A Transition From Disease to Health
2. Heart – Brain Integration
3. Imaging / Omics / Regeneration / Life Style
Complex CAD (5) PVD-P
Valv. – CM AF
Sub-Clinical Arterial (2) DBD/Frailty (3/4)
Health Political (1) Personal (3)
1980 1990 2000 2010 2015
1990 2000 2010 2015 2020
3). Frailty: The Hallmarks of Aging
Non-specificExtreme fatigue, unexplained weight loss, frequent infections.
FallsSo-called hot fall is related to a minor illness that reduces postural
balance below a crucial threshold necessary to maintain gait integrity. Spontaneous falls occur in more severe frailty.
DeliriumRapid onset of fluctuating confusion and impaired awareness. Delirium
is related to reduced integrity of brain function and is independently associated with adverse outcomes.
Fluctuating disabilityFluctuating disability is day-to-day instability.
A Clegg et al., Lancet 2013; 381:752
J Afilalo et. al. JACC 2014;63:747 (Quebec, NY, Boston, NC)
Aging / Frailty
Oxidative Stress on Telomere
B Niemann et. al. JACC 2011; 57: 577. R Madonna, R De Caterina et. al EHJ 2011;32:1190 (Houston &Chieti, Italy)JC Kovacic, EG Nabel, V Fuster – Circ. 2011;123:1650
1
2
4
3
Cell/Molecular Pathways & Aging
CB Newgard et. al. J Clin Invest. 2013;123:946
With Aging, Stress, DNA Damage & Telomere
Shortening Weaken The Multiple Systems
V Gorbunova et. al. Science 2014;346:1187
Oxidative Stress & Telomere Attrition
C Lopez-Otin et. al. Cell. 2013;153:1194 – CV RFs….F Fyhrquist et al., Nat Rev Cardiol 2013; 10:274 – CV RFs….
Senescence Assoc. Secret. Phenotype (SASP)
Chronic Diseases And Disabilities
T Tchkonia et. al. J Clin Invest. 2013;123:966
J Afilalo et. al. JACC 2014;63:747 (Quebec, NY, Boston, NC)
Oxidative Stress & Environment
F Fyhrquist et al. Nat Rev Card. 2013; 10:274
PESA (V Andres, V Fuster et al) 2015
Telomere Attrition & Shortening
•Smoking•Obesity•Sedentary lifestyle•Mental stress / Depression
Inhibition Of Telomere Shortening
•Healthy lifestyle
Telomere Length, Oxidative Stress & Risk Factors
Resulting In Accelerated CV Ageing
M Muller et. al. Eur Heart J. 2014;35:3245
Recent Studies - Dementia Epidemic
Study Data Source Factors
Manton et al. National long-term care Higher educational level,(United States) survey interviews, decline in stroke
1982-1999 incidence
Langa et al. Ongoing population-based Higher educational level;(United States) survey of people 51 yr combination of medical,
of age lifestyle, demographic,and social factors
Schrijvers et al. Population-based cohort Higher educational level, re-(Rotterdam) 55 yr of age in 1990, duction in vascular risk,
extended in 2000 decline in stroke incidence
Qiu et al. Cross-sectional survey of Favorable changes in risk(Stockholm) people 75 yr of age, factors, especially
1987-1989 and 2001- vascular risk; healthier2004 lifestyles
Matthews et al. Survey interviews of people Higher educational level,(England) 65 yr of age, 1989- better prevention of
1994 (in CFAS I) and vascular disease2008-2011 (in CFAS II)
EB Larson et al., NEJM 2013; 369:2275
Induction of Mitohormesis Antioxidant Compensation to ROS
JK Liao Eur Heart J. 2012; 33: 1299
J Bouitbir et. al. 2012; 33: 1397
Sirtuins (SIRT) - Targets for DeacetylationSuppress Reactive Oxygen Species on Mitochondria.
L Guarente N Engl J Med 2011;364:2235
J Couzin-Frankel Science 2011;334:1194
John O’Keefe May-Britt Moser Edvard Moser
A. Petherick. Lancet 2014;384:1333
TAN SNIP Projects
TRANS-ATLANTIC NETWORK TO STUDY STEPWISE NONINVASIVE
IMAGING AS A TOOL FOR CV PROGNOSIS & PREVENTION
1. A Transition From Disease to Health
2. Heart – Brain Integration
3. Imaging / Omics / Regeneration / Life Style
Complex CAD (5) PVD-P
Valv. – CM AF
Sub-Clinical Arterial (2) DBD/Frailty (4/4)
Health Political (1) Personal (3)
1980 1990 2000 2010 2015
1990 2000 2010 2015 2020
c
?
4). To Stimulate a Focus
in the Brain (?)
To Change Life Style
A
Health / Behavior
4a) Science, Health, Education (SHE)
2 . CB
Marketing / IIIP Group / PPPI
“Extended healthy lives” in part due to medical research
generates dramatic returns - Albert & Mary Lasker Found.- 2002
4b) FUSTER-CNIC-FERRER POLYPILL, 2ary PREVENTION, CV EVENTS
Approved in 22 Countries
FOOD INTERACTION
PHARMACOKINETIC INTERACTION WITH ASPIRIN
PHARMACOKINETIC INTERACTION WITH
SYMVASTATIN
PHARMACOKINETIC INTERACTION WITH RAMIPRIL
PHARMACODYNAMIC INTERACTION WITH ASPIRIN
PHARMACODYNAMIC INTERACTION WITH
SYMVASTATIN
PHARMACODINAMIC INTERACTION WITH RAMIPRIL
BIO-EQUIVALENCE
ASA, Statin, ACE-Inhibitor ArgentinaBrazilParaguayItalySpain
FOCUS 1 & 2
FREEDOM
EU 2020
AETNA
JACC , Nov 18, 2014
- 1.
STUDY SITES
64 Clinical Sites - Spain, Italy, Argentina, Brazil, Paraguay
(Ambulatory Clinics And Hospital-based Clinic Sites)
CONCLUSIONS
• FOCUS Phase 1: has identified, from five different countries, five reasons that impede appropriate adherence to CV medications in a post MI population: depresion, social support, degree of insurance, complexity of treatment and age
• FOCUS Phase 2: has shown that, compared with the three drugs given separately, the use of a polypill strategy significantly increases medication adherencefor secondary prevention post-AMI.
• NEXT: What is the effect, post-MI, of a polypill strategy on cardiovascular outcomes?
2. MEETING TARGETS FOR RISK FACTOR CONTROL?
Risk Factors - Proportion of Participants at Goal % – 1 year
Trials LDL SBP DBP Hb A1C Meet Goals
Base FU
BARI-2D 75 56 70 52 14 20
COURAGE 51 55 55 59 12 19
FREEDOM 55 63 53 55 12 20
Freedom, Bari-2D, Courage Investigators, JACC 2013;61:1607PURE (S Yusuf et al.) Lancet 2011; Aug 28 - Poor Countries,7% !!!NHANES, AHA, NHLBI-JNC-7, NHLBI-NCEP P Muntner, V Fuster et al., AHJ 2011; 161: 719 – 49 seconds !!!!
3.
4. Time to Major Cardiovascular Event by Adherence Levels (Post-MI Study)
Sameer Bansilal et al.: ESC 2014 Registry Hotline Aug 31, 2014
Post- MI 1/10/10-2/28/13
N=14,119
AETNA Commercial & Medicare Advantage Population Databases
43%
51%
26%
1. A Transition From Disease to Health
2. Heart – Brain Integration
3. Imaging / Omics / Regeneration / Life Style
Complex CAD (5) PVD-P
Valv. – CM AF
Sub-Clinical Arterial (2) DBD/Frailty (4)
Health Political (1) Personal (3)
1980 1990 2000 2010 2015
1990 2000 2010 2015 2020
