Eurasian Forum Slides "The Modern Understanding of Statins from the Interventional Cardiology Point of View"

Atheroregression Below Glagov Threshold
as New Target of Lipid-Lowering Therapy
From Interventional Cardiology Point of
View
Dr. Alexander Kharlamov
De Haar Research Foundation, Rotterdam, the Netherlands, NY, NY, USA
3rd Department of Internal Medicine/ Ural Institute of Cardiology, Ural
Medical University, Yekaterinburg, Russia
Scientific and Educational Center “Perspective”, Ural Medical University,
Yekaterinburg, Russia
October, 9th, 2015, Eurasian Forum “Medicine, Pharmacy and Public Health”,

Outlines
• Cardiovascular burden in Russia
• Russian national risk factors
• Lipid-lowering strategy and statins
• Regression of atherosclerosis
through the century
• Nanotechnologies for interventional
cardiology
• Frontiers of theranostics of

Part I
Cardiovascular Burden in
Russia
Yekaterinburg, Russia, 2013
6,233 QCAs in 4 PCI centers per
year
2,877 PCIs (any excl. QCA) per
year
2,581 stents implanted per year
Ural Medical

CVD Burden Across the Globe
Adapted from The WHO/ U.S. CDC’s Atlas of
Heart Disease and Stroke, 2015
CVDs are the number 1 cause
of death globally: more people
die annually from CVDs than
from any other cause.
An estimated 17.5 million
people died from CVDs in 2012,
representing 31% of all global
deaths. Of these deaths, an
estimated 7.4 million were due
to coronary heart disease and
6.7 million were due to stroke.
Over three quarters of CVD
deaths take place in low- and
middle-income countries.
Male
Female
Nichols M, EHJ 2014

CVD Burden in Russia
1,020,000-
3,100,000
480,000-
1,020,000
270,000-
480,000
130,000-
270,000
0-130,000
CVD burden in Russia,
total, 2012
631,852 in Sverdlovsk
oblast
Total Mortality in Russia (per 1,000)
– highest in Europe (!):
CVD mortality 915.1 (male) vs 516.8
(female) per 100,000
CAD mortality 500.9 (male) vs 245.5
(female) per 100,000
Adapted from Nichols M,
et al, EHJ 2014
Adapted from Müller-Nordhorn J,
et al, EHJ 2008
Mortality

Shorter Lifespan, and Younger Age of
First ACS Manifestation in Russia
Adapted from Bokeria L,
>70
65-70
63-65
60-63
<60
CVD Mortality by Age
in Russia
Adapted from Norheim
OF, et al, Lancet 2015

CAD Burden vs Quality of Life in
Russia
Economic rating of
Russian regions, 2013
www.riarating.ru
CAD burden in Russia
per 100,000, 2012
et al, 2014
2,571.0 in Sverdlovsk oblast
3,317.7 in Ural Federal District
8,500-
11,700
6,000-
8,500
4,800-
6,000

• 205,902 QCA (63.6% of interventions)
in 175 PCI centers
• 75,378 PCIs (23.3% of interventions)
in 169 PCI centers:
33,600 PCIs in ACS patients in 162
PCI centers
69.8% of patients with MI, and
31.2% of patients with angina
• 531 PCIs per 1,000,000 population
(vs 1,871 in Europe)
• 101,451 stents (1.37 stents per PCI):
System
32,552,622 CVD patients (22.2% of the population) in Russia
(2012)
7,344,255 (22.6% of CVD patients, or 5.0% of the
population) of them with CAD in Russia (2012)
et al, 2014
Endovascu
lar
interventio
ns
CABG
0%
(29,21
4)
No
interventi

PCI and Stenting in Russia
18,000-
19,515
3,600-
18,000
1,000-
3,600
200-
1,000
0-200
PCI in Russia, no. per
year, total, 2013
Mosc
ow
Saint-
Petersburg
6,677
Yekaterinbur
g
0
20000
40000
60000
80000
100000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
PCIsperyear,total
90,335 PCIs (+19.8% per
year), n=185
0
20000
40000
60000
80000
100000
120000
140000
Stentsperyear,
total
124,006 stents
(+18.2%), n=185:
56,438 DES (45,5%)
33.…
57.…
40.…
36.…
64.…
73.…
40.… 34.…
All-cause mortality: CRT (n=9,470) vs
Observational (n=182,901)
Kirtane AJ, et al, Circulation 2009

IVUS, OCT and FFR Guidance
IVUS vs QCA, n=26,503
Adapted from Ahn JM, et al, Am
Adapted from Prati F, et al,
EuroIntervention 2012 (CLI-OPSI study)
Courtesy of St Jude Medical

Stenting in Ural Federal District
9,221 stents at 14 PCI centers per year
et al, 2014
Rank
ing
PCI Center (n=185)
Stenting,
no., total
8
Federal Cardiac Center,
Chelyabinsk
1,637
11
Ural Institute of
Cardiology, Yekaterinburg
1,447
14
District Cardiac Center,
Surgut
1,282
15
Cardiac Center of RAMS,
Tyumen
1,260
36
New Hospital,
Yekaterinburg
672
37
Regional Hospital,
Yekaterinburg
641
41
Municipal Hospital #4,
Nizhny Tagil
616
54
District Hospital, Khanty-
Mansiysk
546
80
Municipal Hospital #3,
Chelyabinsk
440
1.14 PCI centers per 1 million of population
(7.6% of Russia)
792.4 PCIs per 1 million of population
3,000-
3,200
2,500-
3,000
2,000-
2,500
1,500-
2,000
0-1,500

Market of Stents in Russia
124,006 stents at 185 PCI centers per year (56,438, or
45.5% DES) with a 18.2% annual growth
et al, 2014
64%
19%
9%
8%…
55%
31%
8%
6%…
Quantities in
2010
No. sold stents
Qualities in
2010
Sales turnover
First Russian DES
CALIPSO (Angioline)
e-CALIPSO trial, 2016
4% Russian stents:
• BMS Sinus L316
(Angioline, Russia)
• BMS Sinus CoCr
(Angioline, Russia)
• DES Calipso CoCr
(Angioline, Russia)
• BMS and DES
(Stentonic, JSC)

Bioresorbable Scaffolds in Russia
Adapted from Mironov VM, et al, Russian Electronic
Journal of Radiology 2013;3(3):71-75
First experience in Russia, Absorb BVS, Abbott
Vascular, August, 2012
Since July 2013 implanted at least 250
Before After
First Russian
BRS in
development with
support of
Skolkovo Biomed

Russian National Risk
Factors
Part II
First Regional Hospital,
Head of Interventional Cardiology –
Dr. Sergey Chernyshov, MD
2,567 QCAs per year (20th in Russia)
694 PCIs per year (37th in Russia)
641 stents per year
www.okb1.ru
First Regional

Major ‘National’ Risk Factors in
Russian Population
• Chronic stress/
Depression
• Smoking (2786
cig a year)
• Obesity
• Alcohol abuse
(11.6 L a year)
• Low physical
activityAdapted from Report of Russian Ministry of
Health, 2015
24.30
%
19.60
%
1.80%
16.70
%
17.30
%
20%
-10.00% 10.00% 30.00%
Per cent of screened population

Irrational Diet and Obesity in Russia
Jahns L, et al, Eur J Clin
Nutrition (Nature) 2002
Obesity in males
Obesity in females
Carbohydra
tes
FatProtein

U-shaped Relationship Between
Physical Activity and Heart
Adapted from Sharma S,
et al, EHJ 2015
Adapted from Merghani A, et al, Trends
Cardiovasc Med 2015
MET =individual's energy expenditure while
sitting quietly for 1 min
(equivalent to about 1.2 kcal/min for a person
weighing 72 kg)

Alcohol Consumption and CVD
Mortality: U-shaped Curve
Adapted from Marmot MG, et al, Lancet 1981,
Int J Epidemiology 2001
10-year mortality
Adapted from O’Keefe JH, et al, JACC 2007
One "drink" contains 10-15 grams of alcohol
(ethanol): approximately 12 oz. of beer, 4-5 oz.
of wine, 1.5 oz. 80-proof liquor, or 1 oz. 100-
proof liquor
Adapted from Zaridze D, et al, Lancet 2014
Adapted from Hao G, et al,
Angiology 2014

Wine vs Beer
Adapted from Castelnuovo AD, et al, Circulation
2002
RRs or odds ratios for different categories of
wine intake (dose-response curves), as reported
by the original investigators
RRs or odds ratios for different categories of
beer intake (dose-response curves)
Adapted from Grønbæk M, et al, Ann Intern Med
2000

Tobacco and E-Cigarettes
Adapted from The WHO/ U.S. CDC’s Atlas of Adapted from Eurobarometer/ European

Lipid-Lowering Strategy and
Statins
Part III
Ural Institute of Cardiology,
Dr. Michael Perminov, MD
2,560 QCAs per year (21st in Russia)
1,447 PCIs per year (11th in Russia)
1,230 stents per year
www.cardio-burg.ru
Ural Institute of

Lipids and Global Lipid-Lowering
Market
Adapted from The WHO/ U.S. CDC’s Atlas of
Heart Disease and Stroke, 2015

Russian Market of Statins
5 Statin Drugs, 46 Brand and Generic Names, 32 Manufactures –
€ 5,383,667 with a 18.95% annual growth (2011)
Only 6% of CAD patients in Russia treated with statins (estimated
market size € 206,693,564)
Adapted from Pugach IM, Good Clinical Practice
40.9
6%
31.6
9%
26.1
2%
0.89
%
0.34
%
Atorvastat
in
15
generics
Simvastati
n
23
generics
Rosuvasta
tin
1 generic
Fluvastati
n
No
generics
Lovastatin; 4
generics
Quantities in 2011 (No.
sold statins)
Qualities in 2011 (Sales
turnover)
38.6
4%
51.0
2%
8.69
%
1.57
%0.08
%
Atorvastat
in
15
generics
Simvastati
n
23
generics
Rosuvasta
tin
1 generic
Fluvastati
n
No
generics
Lovastatin; 4
generics
Drug
store
77%
Hospit
al
4%
Social
securit
y
progra
m
19% Mean
Cost
€ 5.21
per month

Lipid-Lowering Strategy
A 50% or more of patients discontinue statins within
1 year of treatment initiation
Side effects of statins occur in 18-20% of people
FDA is advising consumers and health care
professionals that:
• Routine monitoring of liver enzymes in
the blood, once considered standard
procedure for statin users, is no longer
needed. Such monitoring has not been
found to be effective in predicting or
preventing the rare occurrences of serious
liver injury associated with statin use.
• Cognitive (brain-related) impairment,
such as memory loss, forgetfulness and
confusion, has been reported by some
statin users.

CAD Prevention and LDL-C: The
Lower The Better?!
Adapted from Raymond C, et. Al, Cleveland Clinic Journal ofAdapted from DuBroff R, et. Al, World J Cardiol 2015
The hypothesis that lowering cholesterol lowers mortality from CAD is
not supported by many clinical research studies
Often overlooked is the fact that numerous studies of cholesterol
lowering have failed to demonstrate a mortality benefit and the
benefits of statins may have been overstated
The Mediterranean diet has consistently lowered cardiovascular
events and mortality in numerous studies and does not typically
lower cholesterol levels
Alternative theories of atherosclerosis are independent of cholesterol

Immunity, Stem Cells, and
Atherosclerosis
Adapted from Hansson JK, et al,Adapted from Tall AR, et al, Nature
Adapted from Weber C, et al, Nature
2008
Adapted from Dotsenko O, et al,
Open Cardiovasc Med J 2010

Adventitia and Atherosclerosis
Adapted from Frink RJ, et
al, 2002
a 43-year-old white male who died in the hospital of
cardiogenic shock following an AMI
Adapted from Maiellaro K,
et al, 2008Adapted from Akhavanpoor M, et al,
Adventitial tertiary lymphoid organs (ATLOs)
in atherosclerosis
Adapted from Mohanta SK, et al, Front
a 24 week old Ldlr−/− mouse fed a
Western diet for 16 weeks
Adapted from Campbell KA, et al,

NSAIDs, CsA, Atherosclerosis and
Cardiovascular Complications
Adapted from Fosslien E, et al, Adapted from Kockx M, et al,

Mediterranean Diet and Mortality
Moderate consumption of ethanol, low consumption of
meat and meat products, and high consumption of
vegetables, fruits and nuts, olive oil, and legumes (since
the Seven Countries Study of 1950s)
Adapted from Hu FB. N Adapted from Knoops
HALE, SENECA, FINE,
1,507 males and 832
females
Adapted from Estruch R et al. N Engl J
Med 2013

Omega-3 vs Trans Fat
No statistically significant effect of omega-3 on mortality
and CV events
Saturated and Trans fat is harmful in CAD patients
Adapted from The Risk and Prevention Study
Adapted from Din JN, et al, BMJ 2004
Adapted from de Souza RJ, et al, BMJ 2015
Adapted from de Souza RJ, et al, BMJ 2015

Regression of Atherosclerosis
Through The Century
Part IV
New Hospital, Yekaterinburg,
Russia, 2013
Dr. Sergey Kozlov, MD
857 QCAs per year (103rd in Russia)
672 stents per year
www.newhospital.ru
New Hospital

Regression of Atherosclerosis
Through The Last Century
Adapted from Williams KJ, et al, Nature Clin Practice:
• ANIMAL STUDIES: rabbits, primates and pigs
• In the 1920s, Anichkov and colleagues reported that switching cholesterol-fed rabbits
to low-fat chow over 2–3 years resulted in arterial lesions becoming more fibrous with
a reduced lipid content
• The first prospective, interventional study demonstrating substantial shrinkage of
atherosclerotic lesions was performed in cholesterol-fed rabbits and reported in 1957
by Friedman M
• ANIMAL STUDIES: murine models
• the apolipoprotein E (apoE)-null (Apoe–/–) mouse (reported first by Plump AS, 1992),
and the LDL-receptor-null (Ldlr–/–) mouse (reported first by Ishibashi S, 1993)
• Transplantation model (reported first by Trogan E, 2004)
• Nonsurgical models
• CLINICAL STUDIES
• Angiographic paradox: the first prospective, interventional study to demonstrate
plaque regression in humans was carried out in the mid-1960s, in which
approximately 10% of patients (n = 31) treated with niacin showed improved femoral
0
100
200
300
400
500
600
700
800
900
1912
1915
1918
1921
1924
1927
1930
1933
1936
1939
1942
1945
1948
1951
1954
1957
1960
1963
1966
1969
1972
1975
1978
1981
1984
1987
1990
1993
1996
1999
2002
2005
2008
2011
2014
‘Atherosclerosis’
Animal studies
of Anichkow
Animal
studies
of
Friedma
n
Angiogra
phic
paradox
of Ost
Imaging
studies
of
Callister
Tx model
of
Trogan
Mice
studies
of Plump
Mice
studies
of
Ishibashi
Regression of advanced atherosclerotic plaques
in the mouse transplantation model
Trogan E, ATVB 2004
Williams KJ, ATVB 2005

Sunrise of the Atherosclerosis’ Age
In 1958, in an editorial in Annals of Internal Medicine,
William Dock compared the significance of the classic work of
Anichkov (1885-1964) to that of the discovery of the tubercle
bacillus by Robert Koch
Adapted from Dock W, et al,
• Felix Marchand apparently first introduced the term
“atherosclerosis” in 1904, and he suggested that
atherosclerosis was responsible for almost all
obstructive processes in the arteries
• In 1908, A.I. Ignatowski described a relationship
between cholesterol-rich food and experimental
atherosclerosis
•
• In 1910, Adolf Windaus showed that atheromatous
lesions contained 6 times as much free cholesterol and
20 times as much esterified cholesterol as a normal
arterial wall
The Cholesterol Theory of Atherosclerosis was presented by Anichkov first for
the Society of Russian Physicians
(chairman – renowned Prof. Ivan Pavlov) in Saint-Petersburg, and published
Imperial Russia and Institute of Experimental
Medicine, Saint-Petersburg in 1891
Institute of Experimental
Medicine, Saint-Petersburg
under leadership of Prof. Ivan
Pavlov (1890-1936)
Institute of Experimental Medicine,
Saint-Petersburg
Nowadays in memory of the tortured
and sacrificed Pavlov’s dogs

• The first prospective, interventional study to demonstrate plaque
regression in humans was reported in 1967, in which approximately 10%
of patients (n = 31) treated with niacin showed improved femoral
angiograms (Ost CR, et al, Scandinavian journal of clinical and laboratory
investigation Suppl 1967)
• The 'angiographic paradox' was resolved with the realization that lipid
lowering had most impact on risk reduction by the remodeling and
stabilization of small rupture-prone vulnerable lesions (Brown BG,
Circulation 1993).
• In the HDL-Atherosclerosis Treatment Study (HATS), administration of
simvastatin plus niacin lowered LDL by 42% and raised HDL by 26%, in
comparison with treatment with antioxidant vitamins alone or placebo. A
Angiographic Paradox
Angio trials of lipid lowering have shown
angiographic evidence of slight atheroregression in
light of large reductions in clinical events
Adapted from Williams KJ, et al, Nature Clinical Practice
Cardiovascular Medicine 2008
Nicotinic acid + Colestipol (39% of cases
with regression) vs
Lovastatin + Colestipol (regression in 32%)
CT
O
>20
%
39
%
18
%
48
%
>30
%
69
%
>37
%
44
%
>30
%
Lumen
Hemorrha
gic
intramur
al pocket
Displa
ced
fibrou
s cap
Upstr
eam
fissur
e
Exits via
a vent
Features associated with ACS:
1) a fissure, tear, or vent in the
fibrous cap overlying the core
lipid pool
2) mural thrombus adherent at
the site of the fissure
3) bleeding into the core lipid
region
4) severe arterial obstruction
secondary to the composite mass
of expanded plaque and
thrombus
Adapted from Constantinides P, J
Atheroscler Res 1966
HATS trial
(n=160), 2001

Cholesterol and CHD risk
Adapted from Castelli WP, et
al, Am J Med 1985
Each 1% increase
in total cholesterol
associated with a
2% increase in
CHD risk
(Framingham
study, n=5,209)
Adapted from Martin MJ, et
al, Lancet 1986
Each 1%
reduction in total
cholesterol
resulted in a 2%
decrease in CHD
risk
(MRFIT trial,
n=361,662)
Adapted from Verschuren
WMM, et al, JAMA 1995
A 0.50-
mmol/L (20-
mg/dL)
increase in
total
cholesterol
corresponded
to an increase
in CHD
mortality risk
of 12% (The
Seven

Imaging Studies of Atheroregression
Adapted from Koskinas KC, et al, Trends in
Cardiovascular Medicine 2015
Adapted from Räber L, et al, Eur Heart J
2015Adapted from Noguchi T, et al, JACC 2015; theAdapted from Papadopoulou T, et al, JACC

Glagovian Atheroregression in
Imaging Trials
Adapted from
Kharlamov A, et al,
0
10
20
30
40
50
60
70
80
90
100
0
2.5
5
7.5
10
12.5
15
17.5
20
22.5
25
27.5
30
32.5
35
37.5
40
42.5
45
47.5
50
52.5
55
57.5
60
62.5
65
67.5
70
72.5
75
77.5
80
82.5
85
87.5
CUMULATIVEFREQUENCY,%
CHANGES OF PLAQUE BURDEN (PAV) FROM BASELINE TO FOLLOW-UP, %
GLAGOVTHRESHOLD
IVUS PREDICTOR OF
NON-CULPRIT LESION-
RELATED MACE
THIN-CAP FIBROATHEROMA
FIBROATHEROMA
NON-PROGRESSIVE
PROGRESSIVE PLAQUES (PATHOLOGIC INTIMAL THICKENING, FIBROATHEROMA)
PLAQUE RUPTURE
PROSPECT REMODELING
KORSHUNOV’S ARTERY REMODELING22
PROSPECT ARTERY REMODELING23 POSITIVE
CORRELATION
BETWEEN
LUMEN AREA
AND PLAQUE
BURDEN
THRESHOLD OF EEM ENLARGEMENT
LUMEN NARROWING
VIRMANI’SCONCEPTOFTHEATHEROGENESIS
ASTEROID5
(Δ 0.98%, 24 MO, P<0.05)
SATURN10
(Δ 1.3%, 24 MO, P<0.05)
APOAI-MILANO11
(Δ 1.3%, 5 WEEK, P<0.05)
PRE-CLINICAL STUDIES OF
ABSORB BVS12, 15, 16
(Δ 12.7%, 24 MO, P<0.05)
JAPAN-ACS7
(Δ 6.3%, 12 MO, P<0.05)
ZEUS13
(Δ 12.5%, 6 MO, P<0.05)
NANO GROUP NANOM-FIM18
(Δ 30.7%, 12 MO, P<0.05)
FERRO GROUP NANOM-FIM18
(Δ 30.0%, 12 MO, P<0.05)
PLASMONICS17 PRE-CLINICAL STUDIES
(Δ 29.8%, 12 MO, P<0.05)
GLAGOVTHRESHOLD

Role of Statins in Atheroregression
Adapted from Babelova A, et al, Current Adapted from Komukai K, et al, JACC 2014;

Glagov Phenomenon and Plaque
Burden
Adapted from
Kharlamov A, et al, Nissen SE, et al.Glagov S, et al.
GLAGOV’S CONCEPT, 1987 (HISTOLOGY) NISSEN’S CONCEPT, 2003 (IVUS)

ASTEROID, 2006
A 0.8% reduction of plaque burden (-12.5 mm3) with
rosuvastatin 40 mg (n=349, 24 months)
Adapted from Nissen SE,

SATURN, 2011
Adapted from Nicholls SJ,
-
1.22
-
0.99
P=0.1
7†
P<0.001
* P<0.00
1*
Median Change Percent Atheroma
Volume
-4.4
-6.4
P=0.0
1†
P=0.0
1*
P<0.0
01*
Median Change in Total
Atheroma Volume
Atorvastat Rosuvasta
63.2%
68.5%
64.7
%
71.3%
P=0.0
2
P=0.07
Percent Atheroma
Volume
Total Atheroma
Volume
Fraction of Patients Exhibiting
Regression

YELLOW, 2013
A 4.6% (-22.5 LCBI a lesion; 24.6%) reduction of plaque
burden with rosuvastatin 40 mg (n=87, 7 weeks)
Adapted from
Gardner, et al,
JACC Imaging
2008
Baseline
Lesion LCBI: 259
Follow-up
Max10mm LCBI: 511
Max4mm LCBI: 802
Lesion LCBI: 177
Max10mm LCBI: 289
Max4mm LCBI: 474
Plaque Area
5.6mm2
Plaque Area
5.5mm2
FFR: 0.78
FFR: 0.74
Adapted from Kini
AS, et al, JACC
2013
Adapted from Puri R, et al,
ATVB 2015
Adapted from Puri R, et al,
ATVB 2015

Japanese Population, and Phenomenon
of JAPAN ACS trial, 2009
atorvastatin 20 mg (n=252, 12 months)
Adapted from Saito S, et
al, InTech 2012
Adapted from Hiro T, et al,
JACC 2009
Baseline Follow-up

Apo-AI Milano, 2003
ETC-216 45 mg/kg (n=36, 5 weeks)
Adapted from Nissen SE,
et al, JAMA 2003

ZEUS, 2014
A 12.5% reduction of plaque burden (-8.2 mm3)
with ezetimibe 10 mg and atorvastatin 20 mg (n=50, 6
months)
Adapted from Nakajima N, et al, IJC

IBIS-2, 2008
A NS reduction of plaque burden (-5.0 mm3) with
darapladib 160 mg (n=175, 12 months)
Adapted from Serruys PW, et

IBIS-4, 2015
Adapted from
Raber L, et al,
EHJ 2015
PROPORTION OF PATIENTS WITH PLAQUE REGRESSION
74%
54%
0
10
20
30
40
50
60
70
80
In one
non-IRA
In both
non-IRA
Baseline
Plaque burden
13months
67.5%
57.8%
%

Composition
The meta-analysis of 9 prospective studies (Banach M, 2015)
comprising 16 statin-treated arms (N=830) indicates a significant
effect of statin therapy on plaque volume, external elastic
membrane, fibrous and dense calcium volumes, while fibro-fatty
and necrotic core tissue volumes remained statistically
unchanged
Adapted from Libby P, et
?
?
Adapted from Banach M, et al,

New Frontiers of Lipid-Lowering
Strategy: PCSK9 vs ApoC3
Adapted from Shimada
Proprotein convertase subtilisin/kexin type 9 inhibitors
Adapted from Shimada YJ,
Antisense therapy targeting
apolipoprotein(a)

ABSORB A study, 2009
Absorb BVS (n=29, 24 months)
Adapted from Serruys PW,
85
90
95
100
105
110
115
120
125
Plaque volume, mm3 (p<0.05):
+4.09 mm3 (NS, p=0.71)
+21.11 mm3 (p<0.0001)
-13.38 mm3 (p=0.0063)

ABSORB B1 and B2 Multi-Imaging
Study, 2014
A 0.05 mm2 gain of plaque burden with Absorb BVS
(n=101, 36 months)
Adapted from Serruys PW, et al,
EuroIntervention 2014
7.5
7.7
7.9
8.1
8.3
8.5
Cohort B1
Cohort B2
Mean plaque area,
mm2 (p<0.0001):

Photoangioplasty of Atherosclerosis
A 4.0% angiographic reduction of artery stenosis with
motexafin lutetium (n=47, 4 weeks)
Adapted from Rockson SJ, et al, Adapted from Chen Z, et al,
Adapted from
Chou TM, et al,
Cath Cardiovasc
Interv 2002

Nanotechnologies for
Interventional Cardiology
Part V
City Private Hospital #41,
Dr. Sergey Berdyshev, MD
249 QCAs per year (160th in Russia)
38 stents per year
www.cardio-centr.ru
Private City

Nanotechnologies in Interventional
Cardiovascular Biomedicine
Adapted from Kharlamov AN L, et al, Future

Photoacoustics In Hands of Nanoparticles
Adapted from Wang B, et al, Biomedical Optics Express 2011; Wang J, et al, JACC 2002; Zynda TK, et al,

Nanoassemblies for Therapy of
Atherosclerosis
Adapted from Lewis DR, et al, WIREs
Nanomed Nanobiotechnol 2011Adapted from Ji X, et al, J Phys Chem C

Nanotechnologies for Management of
Atherothrombosis
Adapted from Al-Jamal
Adapted from Wootton
DM, et al, NEJM 2012
Adapted from Korin N, et
al, Nature 2011
Adapted from Lavik E, et
al, Nature 2012

Drug Delivery and Nanoparticles
Pravastatin with polymer vesicles
Adapted from Broz P, et al, J
Synthetic DiMyristoylPhosphatidylCholine
(DMPC) liposomes with HDL Adapted from
Statin-loaded reconstituted HDL nanoparticles with a 34%
regression of atherosclerosis
Adapted from Duivenvoorden R, et al, Nature Commun 2014

Nanotechnologies in Stents
From ‘Nano Fashion’ to The Nanoparticle and Nanomatrix
Technologies
The SPIRIT Small Vessel Trial
Adapted from Cannon LA, et al, Catheterization and
Cardiovascular Interventions 2011
XIENCE NANO stent system (2.25
20 – 200 nanometers
Strut backbone
Excipients
Courtesy of Kharlamov AN
NanoFIM trial – QCA and IVUS 6 mo FU (n=55)
Adapted from Chen M, et al, Chin Med J 2013;
Yaojun Z, et al, Chin Med J 2014
Nanoparticle-Eluting Stents with a Cationic Electrodeposition
Coating Technology
VEGF Gene-Eluting Stents
Adapted from Yin RX, et al, Theranostics 2014
BMS 28 days Sham NPs-coated
stent 28 days
PTX NPs-coated
stent 28 days
TAXUS 28 days VEGF NPs-coated
stent 28 days
VEGF+PTX NPs-coated
stent 28 days
Adapted
from
Granada
JF, et al,
EuroInterve
ntion 2015
BMS
implantatio
n
Drug
delivery in
ISR setting
(28 days)
De novo
vessels

Nanotechnologies for Plasmonic
Photothermic Therapy of Atherosclerosis
Courtesy of Kharlamov AN; partly adapted from Courtesy of Kharlamov AN
0
200
400
600
800
1000
1200
1400
1600
1800
2000
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
NumberofPublicationsinPubmed
NANOM project (NCT01270139)
NANOM bench stage
(PLASMONICS)
NANOM
FIM
NANOM FIM
follow-up
2012
Dr. Alexander
Kharlamov
De Haar
Research
Foundation, the
Netherlands
PPTTA
2014
Prof.
Stanislav
Emelianov
Texas
University of
Texas at
Austin, TX
Photoacoustic
s and PPTTA2010
Prof. Zahi
Fayad
Mount Sinai
MC, NY
Non-invasive
imaging of
coronaries (CT
with targeted
gold NP)
1857
Michael
Faraday
Philos Trans
1857;147:145–
81
Colloidal gold1999
Steven
Oldenburg
Appl. Phys.
Lett 1999. 75,
2897
Infrared
properties of
gold
2003
Naomi Halas
Rice University,
TX
PNAS 2003.
100(23), 13549-
13554
Biomedical
development of
PPTT and Imaging
in Oncology

NANOM-FIM trial, NCT01270139
Published finally in April 2015
Adapted from Kharlamov AN, et
0
5
10
15
20
25
0 10 20 30 40 50 60 70 80 90 100110120
ΔN/N,% Size of nanoparticles, nm
d = 68 ± 41
Blood
exposed
with
0.1 g/L Au
nanoparticl
es
25 µm
0.1 g/L
Au
nanopar
ticles
Saline

Tremendous Regression of
Atherosclerosis
Adapted from
Kharlamov AN et
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Cumulativefrequency,%
Reduction of plaque-media volume (total atheroma volume) at 12 months, mm3
Nano PTEP, n=42, 58.9 (SD 39.2)
Nano ITTP, n=60, 60.3 (SD 39.5)
Ferro PTEP, n=34, 46.3 (SD 22.6)
Ferro ITTP, n=60, 47.9 (SD 25.3)
Stent PTEP, n=40, 0.8 (SD 0.6)
Stent ITTP, n=60, 0.4 (SD 0.8)
p = 0.055 (PTEP)$
p = 0.047 (ITTP)$
Mean reduction of TAV at
12 mo FU (mm3)
6.38 mm3 –
SATURN trial
(24 mo)
14.1 mm3 –
ApoAI-
Milano
(5 weeks)
ASTEROID
trial - 6.8%
(24 mo)
Pre-
clinical
studies
of BVS -
12.7%
(24 mo)
79.4 mm3 –
PLASMONICS pre-
clinical studies
84.1 mm3 – NANOM PCI
“micro-infusion” (preliminary
results)

Pre Post 6 mo 12 mo
Pre 12 mo
stent
stent
stent
stent
68.5%
37.8%
p<0.05
59.9%
Adapted from Kharlamov AN. Nanoscale 2015
Results:
Patient A

Slight
ectasia
12 month FU
BL
6 month FU
Adapted from Kharlamov AN. Nanoscale 2015
Results:
Patient B

VH-IVUS Examination of Lesions
Adapted
from
Kharla
mov AN,
et al,
Nanosc
0
0.1
0.2
0.3
0.4
0.5
Pre Post 12 mo FU
Densecalcium,mm2
Nano PTEP Nano ITTP Ferro PTEP
Ferro ITTP Stent PTEP Stent ITTP
0
0.5
1
1.5
2
2.5
3
Pre Post 12 mo FU
Necroticcore,mm2
0
0.5
1
1.5
2
2.5
3
Pre Post 12 mo FU
Fibrous,mm2
Ferro ITTP Stent PTEP Stent ITTP
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Pre Post 12 mo FU
Fibrofatty,mm2
p<0.01*, #
NS*, # p<0.01*, #
p<0.01*, #
p<0.01*, #, $ p<0.01*, #
p<0.01*, #, $
p<0.01*, #, $ p<0.01*, #, $
NS*, #, $
p<0.01*, #, $ NS*, #, $

An Electronic Stent: The Final Frontier?!
Combination of transient scaffolding, drug delivery,
NIR theranostics and sensors
In vitro and Ex vivo Experiments of Mg Alloy
‘Electronic’ stent

67
Frontiers of Theranostics of
Atherosclerosis
Part VI
Nanocenter of Ural Federal
University, Yekaterinburg
Head of Nanocenter “Modern
Nanotechnologies” –
Prof. Vladimir Shur, PhD
nanocenter.urfu.ru
Convention Center,
Venue of the Eurasian
Forum “Medicine, PharmacyNanocenter of Ural

Progression of Atherosclerosis, and
Targets for Imaging
Adaptive Intimal
Thickening
Fibrous
Intimal xanthoma/ PIT Fibroatheroma
Adapted from Puri R, et al, Adapted from Kharlamov A, et al, Interventional
Adapted from Otsuka F, et al, Atherosclerosis

MicroOCT and Molecular Imaging
Adapted
from Liu
L, et al,
Nature
Adapted from Taruya A, et al, JACC 2015; Aoki
T, et al, Atherosclerosis 2015
PET (VCAM-1)
vs
SPECT-CT
(monocytes)
Adapted from
Libby P, et al,
Tex Heart Inst
Adapted from Quillard T, et al, Circ Res 2012

Novel Intravascular Imaging
Approaches, and Targets
Adapted
from
Quillard T,
et al, Circ
Adapted from Jaffer FA, et al,
Heart 2013
Adapted from Chinetti-Gbaguidi, G. et al,
Adapted from Shimokado A. et al, JACC 2015
(TCT AP)
Conventional OCT
Lipid-Enhanced SWIR
(Short Wavelength
InfraRed) OCT
3D Angio-IVUS (ANGIOCARE)
Bourantas CV, et al. JACC 2013
NIRS-IVUS
NIRS-IVUS-CT
IVUS-OCT
OCT-NIRS
IVUS-TRFS
3D OCT-NIRF
Adapted from Ughi GJ, et al, Int J
Cardiovasc Imaging 2015
OCT-NIRF
Adapted from Lee S, et al, Circ
Cardiovasc Imaging 2014
OCT-NIRF induced by
indocyanine green (ICG)
Adapted from Lee S, et al, Circ

Shear Stress in Atherosclerosis and
Stenting
Adapted from Cunningham KS, et al, Adapted from Koskinas KC, et al, JACC 2012;
Adapted from Jimenez JM, Ann Biomed Eng 2009

Nanofrontiers of Multimodal Imaging
for Needs of Interventional Cardiology
Emelianov S, et al. Theranostics Cormode DP, et al. Radiology 2010
Non-Invasive ImagingInvasive Imaging

How to Deliver Nanoparticles into the
Plaque?
Adapted from Kharlamov AN, et al, Int J
- Targeting
- Stem cells
- Macrophages
- Liposomes
- Ultrasonic
microbubbles
- Injection with a
catheter
- Surgically with
injection, collar
or on-artery
Cricket™ catheter (Mercator Medical
Systems, Inc, San Leandro, CA)
0.5 hours after
liposomes’
infusion
6 hours
24
hours
Adapted from Lobatto ME. ACS Nano 2015
Adapted from Kharlamov AN. Future Cardiology
2013

Near-Infrared and Nano Technologies for
Real Life and Clinical Practice
Adapted from Peplow M,
et al, Nature 2015

Research and Innovations in Russia
Max €1.59 billions available annually for
biomedical science in Russia
Adapted from REUTERS’ G20
Ministry of
Education and
Science; 21.2
bn RUB; 18%
Federal Agency
of Scientific
Organizations;
68 bn RUB;
56%
Russian
Scientific
Foundation;
17.2 bn RUB;
14%
Russian
Foundation of
Fundamental
Research; 12.2
bn RUB; 10%
Russian Art
Scientific
Foundation; 2
bn RUB; 2%

Sometimes It Looks
Like We Go Practice
Underwater Basket
Weaving Without
Understandable
Vector for Clinical
Medicine, But This
Is The Sunrise of
The New Era of
Theranostics in
Interventional
Cardiology, Which
Has a Potential to

The Year of Heart
in Russia, 2015
CVD mortality in
Russia remains
highest in Europe -
660 per 100,000
(Russian Ministry of
Health, September
2015)
Many Thanks For
Your Adherence!
Courtesy of Barker
Illustration (‘Vladimir
Putin’s Blood Bath’), for
London Times, February
2014

After-Party Impressions
From Forum

My morning with the first snow in
Yekaterinburg, and about 33F…Cardiovascular Hall at the
Focus on rivoroxaban in patients with
atrial fibrillation and stroke (Russia
was a part of the ROCKET trial; I
Prof. Izmozzherova (Department of
Pharmacology), De Nachtwacht (The
Night Watch, 1642, Rembrandt van
Prof. Arkhipov (former chief-
cardiologist of Yekaterinburg) and
Adapted from Bock JS, et al, Circulation 2010
Prof. Smolenskaya (chief of cardiology,
Private City Hospital #41), promotion of
generics (77% of medications in Russia
with a focus on KRKA) as a solution for
Russians promote statins in diabetic
patients despite FDA warnings of 2012;
no Alzheimer’s disease and risk of
Culver AL, et al, Arch Intern Med
(JAMA Intern Med) 2012
Intermission, and Expo

85th Anniversary of the Ural Medical
A Sea of Champaign
Some music
Starting Anniversary
celebrations
Gaudeamus igitur
Address of Rector
Magnificus, Prof. Kutepov
Chinese Mission from Harbin,
Heilongjiang
Chinese
everywhere
and this
uneasy
friendship
looks
dangerous
Courtesy of
David
Parkins ‘An
uneasy
friendship’
(The
Economist,
May 2015)
Some
entertainment
And dance…
And again snow with 37F

Conflict of Interest
The slides were not (!)
presented at the
Forum on October 9th
2015 due to personal
boycott of the Ruscist
scientific community
The slides have
published with a DOI
at ResearchGate on
Courtesy of Rick McKee
(‘Putin’s Bear’), for Daryl
Cagle’s Political Cartoonists

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