Residual CV risk: what is this? Role of lipids and inflammation and how to identify the patient

Residual CV risk: what is this?
Role of lipids and inflammation
and how to identify the patient
Prof. Alberto Zambon
University of Padova (Italy)

Alberto Zambon
Residual CV risk: what is this? Role of lipids and
inflammation and how to identify the patient
Speaker's name : Alberto Zambon, Padova
☑ I have the following potential conflicts of interest to report:
Honoraria: Abbott Medical, Amarin Pharma, Inc., Amgen, Daiichi Sankyo, Les
Laboratoires Servier, Mylan, Novartis, Pfizer, Sanofi
Statement of Financial Interest

Residual Vascular Risk: DEFINITION
Residual Risk of macro-vascular events,
including risk from established (such as
unhealthy lifestyles, dyslipidemia, high blood
pressure, high blood sugar and obesity) and
emerging risk factors, that persists in patients
in spite of current evidence-based medical care
Approved by the International Steering Committee members of the
R3i Foundation and endorsed by its Trustees.
Alberto Zambon
Residual CV risk: what is this? Role of lipids and
inflammation and how to identify the patient

2021 ESC Guidelines: LDL Cholesterol: #1 Lipid parameter for screening, diagnosis and management
LDL-C analysis is recommended as the primary lipid analysis
method for screening, diagnosis, and management.
LDL Tg-Rich Lipoproteins
European Heart Journal
(2021) 42, 3227-3337
R Preston Mason et al. Arterioscler Thromb Vasc Biol. 2020;40:00–00. DOI: 10.1161/ATVBAHA.119.313286

STATINS ALONE LOWER LDL-C, BUT SOMETIMES NOT ENOUGH
For more than 20 years, statins have helped millions of people avoid CV events.4 But many very-high-risk patients don’t reach
LDL-C goals with a statin alone.5
Results of lipid-lowering trials‡
2 Cannon CP, et al. New Engl J Med. 2015;372:2387-97. 6 4S Investigators. Lancet. 1994;344:1383-9; 11 Cannon CP, et al. J Am Coll Cardiol. 2006;48:438-45.

An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Effect of Evolocumab on
Key Secondary Endpoint
Patients w/o Diabetes at Baseline
Patients w/ DIABETES at Baseline
Months after Randomization
CV
Death,
MI,
Stroke
0 6 12 18 24 30 36
Hazard Ratio 0.82
(95% CI 0.72-0.93)
P=0.0021
10.2%
12.2%
0 6 12 18 24 30 36
Hazard Ratio 0.78
(95% CI 0.69-0.89)
P=0.0002
6.4%
8.4%
Pinteraction=0.65
Evolocumab
Placebo
Evolocumab= LDL-C≈30 mg/dl (0.8)
Placebo= LDL-C≈90 mg/dl (2.3)
Lipid values are expressed in mg/dl (mmol/L)
Patients with DIABETES at LDL-C 30 mg/dl (0.8 mmol/L) have greater CV risk than
NON DIABETIC SUBJECT at LDL-C 90 mg/dl (2.3 mmol/L)!!!!
Evolocumab
Placebo

Erin A Bohula et al, Circulation. 2018;138:131–140. DOI: 10.1161/CIRCULATIONAHA.118.034032
CV
Death,
Stroke,
MI
+3.6%

How Common Is Residual Inflammatory Risk?

LDL
Lp(a)
HDL Lp(a) IDL VLDL
(remnants)
Lipids and Lipoproteins
Cholesterol Triglycerides (rich lipoproteins)
Chylomicrons
Atherogenic Lipoproteins
Anti atherogenic
INCREASED PLASMA LEVELS OF TG-RICH LIPOPROTEINS:
Visceral obesity, Type 2 diabetes, FCHL, Chronic kidney disease, Polycystic Ovary Syndrome

Lp(a)
Triglycerides (rich lipoproteins)
Chylomicrons
Not Atherogenic –
Bystanders
TG – Dr Jekyll?
IDL VLDL
(remnants)
Highly Atherogenic?
TG – Mr. Hyde?

Photomicrographs show negatively stained lipoproteins from a single patient: Left pictures show very-low-density lipoprotein+ intermediate-
density lipoprotein; Right pictures, low-density lipoprotein. Top, Serum; middle, plaque extract
Havel RJ, Kane JP et al Arterioscler Thromb.1994;14:1767-1774.
VLDL + IDL LDL
PLASMA
ATHEROSCLEROTIC
PLAQUE
EXTRACT
….VLDL+IDL
accounting for 36%
of the lipoprotein
cholesterol from
the atherosclerotic
plaque extracts….
Triglyceride-Rich Lipoproteins Isolated From Human
Coronary Atherosclerotic Plaque - EVIDENCE FROM THE PAST - 1994

Pathophysiology of TG-rich lipoproteins in the
progression of atherosclerosis
LPL, lipoprotein lipase; TRL, triglyceride-rich lipoproteins; TRL-R, triglyceride-rich lipoprotein remnants.
Toth PP et al Vascular Health and Risk Management 2016:12 171–183

Association of nonfasting IDL and VLDL cholesterol (right) and LDL-C
(left) with C-reactive protein (CRP) in 48 250 participants from the
Copenhagen General Population Study.
Varbo A et al.Circulation. 2013;128:1298-1309.
HDL LDL IDL VLDL
(remnants)
Multivariable adjusted association CRP and LDL-C and IDL/VLDL-C
Age,sex, lipid-lowering therapy, smoking, hypertension, diabetes, menopause, and HRT
LDL
LDL cholesterol (mmol/L)
CRP
(mg/L)
1 3 5 7 9 11
2
4
8
16
32
CRP is 6% higher per 1 mmol/L
higher LDL cholesterol
+6%
VLDL IDL
VLDL and IDL cholesterol (mmol/L)
CRP
(mg/L)
1 3 5 7 9 11
2
4
8
16
32
CRP is 36% higher per 1 mmol/L
higher VLDL/IDL cholesterol
+36%
+40 mg/dl 40 mg/dl

Correlation between LDL-C, TG-Rich Lipoproteins
Cholesterol and Carotid Plaque Composition
HDL LDL IDL VLDL
(remnants)
Zambon A et al Atherosclerosis 2013 230:106-109
Association
between
Lipoproteins and
Macrophage
Plaque Content
ap
m ap m
Association between
Lipoproteins and
Smooth Muscle Cell
Plaque Content
r= 0.11, p=ns r=0.15, p=ns
r= 0.62, p<0.01 r= -044, p<0.05
LDL-C
TG-Rich lipoproteins-C

J Am Heart Assoc. 2020;9:e015801. DOI: 10.1161/JAHA.119.015801
CONCLUSIONS: Moderate-to-severe elevation of TG is associated
with a significantly increased risk of all-cause mortality and ASCVD
events in a large cohort of low-to-moderate cardiovascular risk
individuals in a real-world clinical setting.
Event Rates and Adjusted HR for All-Cause Mortality and
ASCVD Events According to Triglyceride Levels
• n= 158 042 individuals
• Normal TG < 150 mg/dl
• High TG: 150-500 mg/dl
• Very High > 500 mg/dl
ASCVD events
Overall Mortality
*age, sex, hypertension, diabetes,
chronic kidney disease (CKD),
previous cardiovascular
hospitalizations, antidiabetic
medication, statin,
antihypertensive,
anticoagulants, total cholesterol,
and HDL-C.

13,015 statin-treated patients from the
Copenhagen General Population Study were
included with 8 years median follow-up.
(J Am Coll Cardiol 2021;77:1439–50)
Elevated TG-Rich Lipoproteins/Remnants

➢ RAISED TRIGLYCERIDES concentrations are an additional causal
risk factor for cardiovascular disease and all-cause mortality
➢ INFLAMMATORY components of atherosclerosis may be modulated
by triglyceride rich lipoproteins – UNSTABLE PLAQUE
Triglycerides, CV Risk and Atherosclerosis: Mr. Hyde
➢ Elevated triglycerides associated with higher CV events and overall mortality in a large Italian
cohort at low-moderate CV risk
➢ In a large statin-treated cohort from the Copenhagen General Population Study, elevated
triglycerides were associated with higher all-cause mortality (+23%) and MI (+82%)

Patient
Phenotype
On optimal
LDL-C control
LDL-C< 100 mg/dl
Sub-clinical
Inflammation
hsCRP 2-4 mg/L
Persistent
TG elevation
≥150 mg/dl
BMI 29.7 BMI 28.5 BMI 30.8
Modest elevation of hsCRP – Subclinical inflammation
Pro- atherothrombotic phenotype
Mild to moderate Hypertriglyceridemia

THANK YOU FOR YOUR ATTENTION!!!

OPTIMAL CONTROL of both LDL-C and TG-Rich lipoproteins
KEY STEP
for an EFFECTIVE MANAGEMENT of
RISK OF CARDIOVASCULAR EVENTS

Residual CV risk: what is this? Role of lipids and inflammation and how to identify the patient

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Residual CV risk: what is this? Role of lipids and inflammation and how to identify the patient