cardiology basics

1. ROLE OF INFLAMATION IN
CORONARY ARTERY
DISEASE
DR.K.ABHISHEK

2. • A role for inflammation in atherosclerosis was suggested in the early 20th century
by Sir William Osler
• elevated white blood cell counts have been known to be associated with CHD as
early as the 1920s
• Maseri and colleagues in the 1980s suggested that high-sensitivity C-reactive
protein (hs-CRP) was increased in patients admitted for acute myocardial infarction
(AMI)
• Ridker and colleagues established a role for CRP in the prediction of CHD events.

3. • For many years, we thought of coronary artery disease (CAD) as a disease of
deposition of atherosclerotic plaque in arteries that ultimately became occluded and
caused either ischemia or an acute myocardial infarction.
• Therapy for CAD focused on lipid lowering to reduce atherosclerosis, and initially
bypass surgery and then PCI to restore blood flow to arteries occluded by
atherosclerotic plaque
• Recent findings have deeply changed the current view of coronary heart disease,
going beyond the simplistic model of atherosclerosis as a passive process involving
cholesterol build-up in the subintimal space of the arteries until their final occlusion
and/or thrombosis and instead focusing on the key roles of inflammation and the
immune system in plaque formation and destabilization

4. • Chronic inflammation is a typical hallmark of cardiac disease, worsening outcomes
irrespective of serum cholesterol levels
• Low-grade chronic inflammation correlates with higher incidence of several non-
cardiac diseases, including depression,
• chronic depression is now listed among the most important cardiovascular risk factors
for poor prognosis among patients with myocardial infarction

6. • Pathological conditions that include common cardiovascular risk factors,
such as hypertension, hyperlipidaemia, hyperglycaemia and smoking, can
elicit immune responses that promote the secretion of leukocyte adhesion
molecules and chemotactic factors, inducing monocyte adhesion to
endothelial cells and transmigration into the subintimal space.
• Initial atherosclerotic lesions begin with the differentiation of monocytes
into macrophages that engulf cholesterol-rich oxidized low density
lipoproteins (ldl-ox) to become foam cells that organize into fatty streaks

7. • The perpetuation of proinflammatory and oxidizing atherosclerotic stimuli results in
the recruitment of further macrophages, mast cells, and activated T and B cells that
increase vascular lesions
• Fibrous atherosclerotic plaque cap maintains its stability due to interstitial collagen.
• Cytokines and inflammatory immune cells interfere with the integrity of the
collagen matrix, impairing the synthesis of new collagen fibers and stimulating the
reabsorption of existing ones through the production and activation of specific
enzymes metalloproteinases
• This process makes the cap weaker and prone to rupture.

8. • The broken cap exposes the athero-necrotic core to coagulation factors and platelets
circulating into the arterial blood and induces arterial thrombosis, thus leading to an acute
cardiovascular event

9. ROLE OF INFLAMMATION IN PLAQUE RUPTURE
• In atherosclerosis, inflammatory cells and accumulation of lipids can lead to the formation
of a lipid-rich core within the intima of arteries
• Lipid core expands, the intima thins, creating a vulnerable fibrous cap between the lipid
core and lumen of the artery
• Proinflammatory stimuli initiate a cascade of events activating interleukin (IL)-1β.
• IL-1β stimulates adhesion molecules, including intercellular adhesion molecule (ICAM)-1
and vascular cell adhesion molecule (VCAM)- 1, and chemokines such as monocyte
chemoattractant protein (MCP)-1 involved in inflammatory cardiovascular disease

10. • IL-1β also induces expression of IL-6, which stimulates hepatocytes to synthesize
prothrombotic acute phase reactants, including fibrinogen and plasminogen activator
inhibitor and CRP.
• Phagocytes recruited by MCP-1 disrupt the atherosclerotic plaque by producing proteolytic
enzymes, which degrade the collagen that support the plaque’s protective fibrous cap,
leaving it prone to rupture.
• When the plaque ruptures, blood comes in contact with prothrombotic factors and
coagulates thrombus formation
• vessel is occluded by the thrombus leading to vascular events such as a myocardial
infarction

12. THE HEART AS AN IMMUNE ORGAN
• The heart can respond to acute tissue injury through complex inflammatory and
reparative cascades, acting as an “immune organ”
• Several types of immune cells, such as macrophages, dendritic cells, mast cells (mcs)
and a small number of B and T lymphocytes, reside in the heart
• Irrespective of the origin of cell injury, acute tissue damage promotes an
inflammatory response, mainly characterized by the involvement of innate immune
cells, followed by a reparative/remodeling phase, with a prevalence of adaptive
immune cells and angiogenic/fibrotic event

13. THE INFLAMMATORY CASCADE IN ISCHAEMIC
MYOCARDIAL INJURY
• Histological patterns that characterize acute myocardial infarction include
coagulative necrosis as the main process, regulated necrosis (necroptosis), and/or
secondary apoptosis.
• Following myocardial infarction cellular fragments released by dying or injured
myocardial cells can trigger resident cardiac immune cells as endogenous
“alarmins,” similar to microbial pathogen-associated molecular patterns (PAMPs) or
damage-associated molecular patterns (DAMPs)

14. • Through the engagement of pattern recognition receptors (PRRS) such as membrane
toll-like receptors (TLRS) and intracellular nucleotide binding and oligomerization
domain (NOD)-like receptors (NLRS).
• In human hearts, TLR2 and TLR4 are the most representative subtypes and,
together with NOD1 and the NLRP3 subtype, have been demonstrated to activate
inflammasomes in the heart and play critical roles in cardiac remodeling following
myocardial infarction and ischaemia/reperfusion damage

16. • Endogenous DAMPS can also activate the complement system, as observed with
increased C3 fragments in infarcted myocardial tissue, promoting leukocyte
translocation in injured myocardium
• Immune activation by DAMPS can arise also from mitochondrial DNA released by
the mitochondria of damaged cardiac cells due to haemodynamic stress, inducing
cardiomyocyte apoptosis.

17. • Additionally, ischemic damage leads to mitochondrial dysfunction, accompanied by
the generation of a large amount of reactive oxygen species (ROS).
• Exorbitant production of ROS impairs myocardial function and activates leukocyte
migration, reducing the number of vital cardiomyocytes and promoting extracellular
matrix degradation

18. • Nuclear factor kb (nf-kb), a highly conserved DNA transcription factor, drives the
production of cytokines, interferons, and chemokines in the myocardial infarction
zone when activated via the TLR and NOD pathways, complement system, and ROS
products
• Interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-A), the main pro-
inflammatory cytokines released in the injured myocardium, mediate the synthesis
of more chemotactic factors that enhance leukocyte recruitment into the infarct area
and play important roles in inflammasome assembly and IL-1b and interleukin 18
(IL-18) maturation

20. • central and autonomic regulation of cardiac functions, namely, the neurocardiac axis,
provides a physiological explanation that links psycho-emotional stressors and social
adversities to acute cardiac events, including myocardial infarction, myocardial ischaemia,
cardiac wall motion abnormalities, and sudden death.
• Psychological distress can precipitate heart function through a dysregulated
neuroendocrine and autonomic response, as demonstrated by increased serum cortisol and
catecholamines, reduced HRV and increased inflammatory cascades.
• Sympathetic hyperactivation can influence cytokine production via the transcription of
NFkB mediated genes involved in pro-inflammatory immune response, thus enhancing
vascular endothelial activation and thrombosis.

22. MAST CELLS AND CARDIAC EVENTS
• Mast (mastoid) cells (MCs) are innate immune cells located in mucosal and
epithelial tissues throughout the body including the brain and heart.
• MCs, accumulating in the arterial adventitial space in response to mechanical or
hypoxic stress, play a critical role in the fibrous cap erosion of atherosclerotic
plaques and in coronary vasospasms induced by vasoactive and inflammatory
mediators

23. • In the first 24 h after an acute ischaemic cardiac event, endogenous DAMPs induce
the release of histamine, TNF- a, IL-6, prostaglandins, leukotrienes, tryptase,
chymase and renin from MCs, leading to an acute immune response (sterile
inflammation)
• MC mediators and DAMPs from necrotic cardiomyocytes induce neutrophil
recruitment, tissue digestion through protease secretion and the phagocytosis of
necrotic cells and induction of apoptosis in live cardiomyocytes, thus amplifying the
inflammatory response

24. SUMMARY: THE BALANCE OF INFLAMMATORY
RESPONSES IN ISCHAEMIC CARDIAC DISEASE
• presence of immune cells in an infarcted area is essential for the initiation of repair
processes in injured cardiac tissue.
• In the first hours after ischaemic damage, the activation of resident immune cells
and recruitment of leukocytes from the circulation aims to remove dead cells,
molecular fragments and debris,
• and release cytokines and growth factors to build highly vascularized granulation
tissue to maintain the integrity of the myocardial wall

25. • Subsequent reparative phase characterizes the days and weeks after myocardial
infarction, with the formation of fibrotic scars and new vessels in the injured area.
• Temporal and spatial regulation of post-infarction inflammatory responses is crucial.
• Patients of different ages with diverse comorbidities (i.E., Diabetes, hypertension)
and genetic characteristics may have different remodeling responses, irrespective of
the size of the myocardial necrosis

26. • Prolonged inflammation or defects in the regulatory feedback of inflammatory
mediators may reduce collagen deposition and provoke dilatation of the cardiac
chambers
• Poor control of the inflammatory reaction may extend the immune infiltrate beyond
the non infarcted myocardium, increasing matrix protein deposition and worsening
fibrosis and diastolic function
• Identifying a high-risk pattern of circulating inflammatory cells may have
prognostic value for secondary prevention in ischaemic patients.

27. THE HEART AS AN ENDOCRINE GLAND
• middle of the last century, granules similar to those found in endocrine cells were
detected for the first time in the cardiac atria,
• and their ability to lower blood pressure through potent diuretic and natriuretic
effects was proven at the end of the 1970s.
• Only in the early eighties were the granules also identified in other tissues and
classified into three main subtypes: atrial natriuretic peptide (ANP), brain
natriuretic peptide (BNP) and type C natriuretic peptide (CNP).

28. • recently, the discovery of other endocrine molecules (collectively named cardiokines)
released by cardiomyocytes, fibroblasts, vascular endothelial cardiac cells and
immune cells was a significant advance in research investigating the endocrine
properties of the heart
• Any haemodynamic condition determining atrial distention like volume expansion
with saline solution, water immersion, postural changes, a high quantity of ingested
salt, fluid overload due to diastolic cardiac impairment increases ANP release into
the bloodstream.

29. • Chemical stimuli such as endothelin, platelet activating factor, corticotropin-
releasing hormone (CRH), and glucagon-like peptide can also trigger the synthesis of
ANP
• Brain natriuretic peptide (BNP), originally described in the pig brain, is highly
expressed in the ventricular myocardium and responds to ventricular wall
distension due to volume or pressure overload
• C-type natriuretic peptide (CNP) is diffused throughout the central nervous system,
as well as in the vascular endothelium.
• This peptide exerts a weak endocrine natriuretic effect and acts as a paracrine factor
for the control of vascular tone

30. CAN INFLAMMATORY BIOMARKERS IMPROVE
OUR ABILITY TO PREDICT CHD?
•Few inflammatory markers in CAD

31. HIGH-SENSITIVITY CRP
• produced mainly by the liver and also by adipocytes and vascular smooth muscle
cells in response to a rise in interleukin-6 & TNF-a
• CRP levels often increase substantially in response to a wide variety of biological
insults, infections, inflammatory conditions and cancer
• CRP has multiple pro-inflammatory and pro-atherogenic properties
• Multiple prospective cohort studies have established that increased hsCRP levels
are associated with increased CHD risk in both genders, across a wide age range

32. • recent meta-analysis of individual records of 160,309 people without a known history
of vascular disease from 54 long-term prospective studies showed that serum CRP
concentration has continuous associations with the risk of CHD, ischemic stroke and
vascular mortality
• Many factors influence CRP- infection,obesity ,autoimmune diseases etc
• smoking cessation, losing weight, exercise also decrease serum CRP levels.
• Several medications, including aspirin and clopidogrel, and, in particular, statins,
are also known to reduce serum CRP levels

33. LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2
• platelet activating factor-acetyl hydrolase (PAF-AH), belongs to a family of A2
phospholipases
• It catalyzes oxidized phosphatidylcholine into oxidized non-esterified free fatty acids
and lyso-phosphatidylcholine in the plasma, exerting a pro-inflammatory effect
believed to be involved in atherogenesis.
• secreted into the plasma by hematopoietic cell and is then transported mainly by
LDL (80–85%), and in lesser amounts by HDL and lipoprotein (a).

34. • Lp-PLA2 enzyme can be measured based on its mass or enzymatic activity
• Lp PLA2 correlated with age, male gender, smoking and LDL cholesterol levels and
are reduced significantly by statins
• large meta-analysis using individual data from 79,036 participants in 32 prospective
studies showed that both Lp-PLA2 activity and mass predicted risk of CHD and
vascular death

37. • The findings were endorsed by the Women’s Health study, involving 39,876 healthy
postmenopausal women, which showed that those with highest levels of CRP had five
times the risk of developing CVD and seven times the risk of having a heart attack or
stroke compared to subjects with the lowest levels (JAMA 2002, 28; 288:980-7).
• C-reactive protein (CRP), a marker of the inflammatory process, has been a
forerunner in the search for inflammatory markers. In the Physician’s Health study
involving 22,071 healthy middle aged men (1997) it has been shown that those in the
highest quartile for CRP had three times the risk of future MI and twice the risk of
future ischaemic stroke in comparison to those in the lowest quartile (NEJM
1997;336: 973-9).

38. • In the JUPITER study, it was demonstrated that rosuvastatin (a statin known to
reduce both LDL cholesterol and CRP) reduced risk of MI and stroke in patients
with low levels of cholesterol and high levels of CRP (N Engl J Med 2008; 359: 2195-
2207). Here due to the dual effects of statins it was impossible to disentangle
benefits arising from reducing cholesterol from those due to anti-inflammatory
effects.
• This left the question of whether targeting inflammation on its own represented a
viable treatment for decreasing the risk of atherosclerosis unanswered.

39. CANTOS (CANAKINUMAB ANTI-INFLAMMATORY
THROMBOSIS OUTCOMES STUDY)
• 10,000 patients, set out to test whether blocking the pro-inflammatory
cytokine interleukin -1ß (IL1ß) with canakinumab, in comparison to
placebo, reduces the rate of recurrent MI, stroke and cardiovascular
death among MI patients who remain at high risk due to persistent
elevation of the inflammatory biomarker CRP (=2mg/L) despite
receiving the best medical care

40. • Canakinumab is a subcutaneously injected interleukin (IL)-1β blocker FDA in 2009
for the treatment of cryopyrin associated periodic syndromes, specifically
autoinflammatory syndrome and Muckle-Wells syndrome
• Although several other medications have proven to be effective in reducing ASCVD
events in high-risk patients while also affecting hsCRP to varying degrees, these
drugs possess other mechanistic benefits that contribute to their ASCVD event
reduction.
• Methotrexate is a strong hsCRP-lowering drug but does not have a major clinical
trial assessing ASCVD events, although preliminary meta-analytic data look
promising

41. • Canakinumab is a novel therapy for the prevention of ASCVD events because it
demonstrated a pure anti-inflammatory effect by significantly reducing hsCRP with
no effect on LDL-C or HDL-C.
• By purely targeting the inflammatory component of ASCVD, canakinumab further
reduces ASCVD events and is a potential add-on therapy.
• The limiting factor for access to canakinumab currently is cost.
• Canakinumab is not likely to reach acceptable cost-effectiveness without substantial
discounting of the drug’s current price and should not be generally recommended in
the interim.

42. TRADITIONAL DRUGS TO SUPPRESS
INFLAMMATION AND REDUCE ASCVD RISK
• Many agents have been shown to suppress hsCRP concentrations, including cyclo-
oxygenase (COX) inhibitors, corticosteroids, renin-angiotensin system inhibitors, fibric
acid derivatives, statins, and methotrexate
• agents such as allopurinol, cholchicine, biological therapies (tumor necrosis factor
inhibitors)
• agents targeting lipid mediators (phospholipase inhibitors and antileukotrienes)
• intracellular pathways (inhibition of NADPH oxidase, p38 migoten-activated protein
kinase, or phosphodiesterase) are either already in use for the treatment of anti-
inflammatory diseases or are under development and evaluation