Cardiovascular Pharmacology Flashcards
(148 cards)
1
Q
What is angina and when were drugs developed to treat it?
A
Angina= blockage of the coronary arteries that causes pain (unstable) during exercise but is relieved at rest (stable)
Causes lack of perfusion due to lesions, arterial contractions or blood clots.
Beta antagonists and calcium channel blockers were developed during the 1950s and 1960s to help treat angina
2
Q
What increases contractions and activity of the heart?
A
Adrenalin and noradrenalin increase the contraction of the heart
Calcium causes an increase in heart muscle activity
3
Q
What do adrenalin and noradrenalin act through, and what type of receptor is it?
A
Act via alpha and beta adrenergic receptors, which are GPCRs
4
Q
By who and when were beta blockers introduced?
A
1964
The first beta blocker to be developed and introduced for clinical use was propranolol. Propranolol was discovered by British pharmacologist Sir James Black, who later won the Nobel Prize in Physiology or Medicine in 1988 for his discoveries concerning “the development of beta-blockers as a treatment for heart disease.”
5
Q
What effects does adrenaline have on different tissues?
A
Adrenaline is part of the fight or flight response and thus has different actions on different tissues. E.g. it relaxes the gut but causes contractions in the heart
These different responses are due to the different receptors.
6
Q
How are adrenoceptors categorised?
A
Split into classes based on agonist potency
And subclasses based on antqgonist selectivity
7
Q
How was propanolol created?
A
In the 1950s, it was found that beta-receptos could be blocked by dichloririsoprenaline. This had no clinical utility due to the chlorine attached however
Removal of the chlorine created pronethalol, however this caused carcinogenesis in mice
Pronethalol was modified and an oxymethylene group was included to create propanolol in 1964. This had a higher potency but fewer side effects.
8
Q
Why was the creation of propanolol so special?
A
- The discovery of propanolol was the first new treatment for angina for almost 100 years. It became the worlds biggest selling drug
- It was hailed as the greatest breakthrough in the treatment of heart disease since the discovery of digitalis
- The drug also demonstrated that new major classes of drugs could be developed by applying basic knowledge of receptor-driven cell signalling systems to clinical problems.
9
Q
What is a side effect of propanolol?
A
It is not a selective beta blocker and blocks both beta-1 and 2 adrenergic receptors
This meant it could produce off target side effects e.g. in the airways
10
Q
Since propanolol, what other beta-blockers have been created?
A
Atenolol- beta-1 selective drug also used to treat osteoporosis, infection and metastatic caner
Nebivolol- beta-1 selective that can stimulate the kidney to cause diuresis and vasodilation, reducing BP
Long acting and short acting beta-blockers also been developed
11
Q
What do beta-blockers bind to?
A
They bind to the same site as catecholamines through hydrogen bonding which is reversible
12
Q
What gives beta-blockers the flexibility to fit into the binding site?
A
The oxymethylene bridge gives it flexibility so it can fit into the binding site.
13
Q
Through what pathways do beta-blockers act?
A
Beta receptors are linked to the Gs protein, however evidence has been published that they also act through the beta-arrestin pathway
Kim et al. found that in addition to its antagonist activity, alprenolol stimulated β1-AR-mediated activation of the epidermal growth factor receptor (EGFR) and activation of extracellular signal-
regulated kinase (ERK) through beta arrestin pathways
Both an antagonist and an agonist
The therapeutic benefits of these drugs may be the result of their dual activities–inhibition of G protein signaling and promotion of β-arrestin-mediated signaling, which activates a pathway that has been implicated in cardioprotective effects of β1-AR signaling
New drugs are being tested that exploit ligand dependent signalling bias.
14
Q
What are calcium channel blockers used for?
A
Calcium channel blockers (CCBs) are a class of medications primarily used to treat various cardiovascular conditions by blocking the influx of calcium ions into cardiac and smooth muscle cells through voltage-gated calcium channels. By doing so, they dilate blood vessels and reduce the workload of the heart
15
Q
How was it discovered that calcium was required for contraction and that CCBs were useful?
A
Concentration-response curves found that decreasing the concentration of calcium reduced contraction in rabbit mesenteric artery (1969, Godfraind and Kaba).
Fleckenstein et al then did a study on verapamil and found it produced similator curves to decreasing calcium concentrations. He used the term calcium antagonist to describe verapamil.
16
Q
What are examples of current CCBs in use?
A
Verapamil, diltiazem, mibefradil and dihydropyridines (e.g. nicardipin)
17
Q
What is the primary route for Ca2+ entry into cardiac, skeletal and smooth muscles
A
- L type calcium channels are the primary route for Ca2+ entry into cardiac, skeletal and smooth muscles
- Different drugs all bind to different sites on the calcium channel
18
Q
How have the death rates rom CVD changed?
A
1950- 307.4 per 100,000 people
1996- 134.6 per 100,000 people
19
Q
What are side effects of calcium channel blockers?
A
Reduced BP
Headache
AV block
Abdominal discomfort
Peripheral oedema
20
Q
What is verapamil selective for?
A
Relatively selective for myocardial Ca2+ channels. Reduces rate and strength of heart contractions
21
Q
What were the top two global causes of death in 2016?
A
Atherosclerosis and ischaemic heart disease
22
Q
What is the basic pathogenesis of atherosclerosis?
A
Response to injury hypothesis=
- Artery trying to repair itself in response to injury. The injury may be accumulation of cholesterol or turbulent blood flow.
- Leukocytes adhere and enter sub-endothial space. Monocytes transform into macrophages and take up lipids turning into foam cells. This is a normal process- babies have fatty streaks.
- If the insult continues it cannot be contained and inflammatory cells build up. Fibrous cap forms over the top of the lipid core
- The smooth muscle starts to release extracellular matrix. Small blood vessels grow and rupture and eventually cap can rupture at the edge of the plaque and cause thrombus to form, blocking the artery
23
Q
What preventative treatment can stop atherosclerosis?
A
Lipid lowering therapy
Via diet- reducing cholesterol or drugs
24
Q
How is cholesterol carried around the body?
A
Cholesterol is synthesised in the liver.
LDL (lipoprotein) transports this to peripheral organs and arteries.
HDL brings it back and removes excess cholesterol
25
What are drugs that affect cholesterol levels in within the digestive system?
Ezetimibe= blocks absorption of cholesterol from the small intestine
Bile acid resins= bile acid resins increase the excretion of cholesterol in the stool
26
What is the best selling pharmaceutical in history?
Statins
Generated $125 billion over ~14.5 years and has made up 1/4 of Pfizers annual income over several years
27
What is the mechanism of action of statins?
It inhibits the rate limiting step of the mevalonate pathway, the cholesterol forming pathway in the liver
28
What study initially assessed the effectiveness of statins and what did it find?
The MRC/BHF heart protection study
1994-2001
Found simverstatin decreased the incidence of major vascular events and reduced total LDL, triglycerides with no difference in HDL levels
29
What are the side effects of statins?
Muscle pain and weakness (myopathy), Rhabdomyolysis, renal failure, liver toxicity and increased risk of diabetes mellitus.
30
What lipid lowering drug is available over the counter?
Statins
31
What are lipid lowering drugs for patients intolerant to statins?
Bempedoic acid and PCSK9 inhibitors
32
How does bempedoic acid work?
- Works on the same pathway as statins, just blocks the pathway higher up
- Blocks the enzyme (ATP-citrate Lyase) that converts citrate to Acetyl-CoA at the start of the pathway
- can reduce cholesterol levels further in a patient already on statins
33
What is the PCSK9 pathway?
PCSK9 is a protein that binds to LDL receptors and targets it to a lysosome, where the receptor is degraded
Inhibition of PCSK9 allows to receptor to be reycled and uptake more plasma LDL
34
What drugs are currently targeting PCSK9 pathway?
Monoclonal antibodies
Include Alirocumab, evolocumab and bococizumab (withdrawn in 2016)
Also siRNA (incliseran
35
What trials have studied the effects of PCSK9 monclonal antibody inhibitors?
The ODYSSEY trial= gave alircoumab 75mg subcutaneously every two weeks to statin intolerance patients
Caused a substantial drop in PCSK9 levels
36
What is incliseran?
A small interfering RNA (siRNA) that interferes with the production of PCSK9
37
What trial studied the effects of incliseran?
The ORION-10 and ORION 11 trials gave incliseran subcutaenously every 6 months to patients that had elevated LDL despitw being on max statin treatment
Reduced LDL by ~50% with only mild adverse events at the injection site.
It was a placebo controlled trial
Study duration was 540 days
38
How has overexpression of PCSK9 helped with studying atheroscleorsis?
Keeter et al 2022
Developed a adenovrial concept which targeted PCSK9 to overexpress it
If combined this with a high cholesterol diet, get a large increase of lipids in animal models artery walls where would would expect to see atheroma to start e.g. the lesser arches where blood is more turbulent
39
How do statins exert their protective effects?
Not only due to lipid lowering effects
Statins have a wide range of effects independent of lipid lowering
It has anti-thrombotic, anti-inflammatory, angiogenesis, anti-oxidant and endothelial function
40
What do statins do to help endothelial function?
Statins opposed the effect of L-NAME, and increased NO concentrations, causing vasodilation and reduced blood pressure
This increased NO reduces inflammatory cell infiltration and SMC proliferation, stopping thickening of atherosclerosis plaques
41
What drug targets inflammation in atheroscelrosis?
Canakinub was a drug that blocked IL-1 beta and used to treated systemic juvenile idiopathic arthritis
It reduced atherosclerotic events
42
How does canakinumab exert its atheroscelrotic-protective effects?
Blocks IL-1Beta
This decreases activation and proliferation in SMCs
Also reduces expression of adhesion molecules and decreases leukocyte infiltration?
43
What trial looked at Canakinumab's effects?
CANTOS trial
Double blind trial that looked at 10,000 patients in 40 countries
3 different doses and placebo given
Significantly reduced CV events independent of lipid lowering
However, there was no overall improvements in survival due to an increased risk of fatal infections
44
What are future targets of preventing/treating atherosclerosis?
MicroRNA are being developed for a range of different pathways to modify specific stages of atheroscelrosis or manage compliations
Effect cholesterol homeostasis, macrophage activation, or alter balance of pro or anti-inflammatory signalling pathways
45
What is an example of a microRNA that is currently being targeted in atherosclerosis treatment?
miRNA 143/45 reduced transcription regulators important in switching vascular SMCs from contractile to proliferative phenotypes
46
What is the pathway that induces arterial relaxation and what can inhibit this?
- Endothelium-dependent, nitric oxide-mediated relaxation can be abolished using pharmacological inhibitors: L-nitroarginine methyl ester (L-NAME) is a competitive inhibitor of nitric oxide synthase which blocks nitric oxide generation in the endothelium.
- Endothelium- independent, guanylate cyclase-dependent relaxation can be produced using nitric oxide donors such as sodium nitroprusside (SNP).
47
How does ACh cause vascular relaxation?
ACh binds to muscarinic (GPCRs) on the endothelial cells
Through activation of Gq enzymes and second messengers are activated, eventually leading to the activation of of endothelail nitric oxide synthase
This produces nitric oxide from L-arginine
NO diffuses to the vascular smooth muscles and induces vasodilation by stimulatinf the production of cGMP, which decreases Ca2+ levels
48
How does noradrenaline cause act in the arteries?
Binds to alpha-1 adrenoceptors in the smooth muscles of blood vessels
Activates a G protein response which eventually releases Ca2+ from intracellular stored
However, in some circumstances, noradrenaline can cause dilation by binding to beta-adrenergic receptors and helping eNOS function
The net effect on vascular tone depends on the balance between alpha and beta receptor activation and the specific context in which noradrenaline is released, but it is predominantly a vasoconstrictor
49
What experimental set up is useful for measurement of smooth muscle function?
Isolated tissue bath
Drugs- adrenergic agonists and antagonists can be used
The primary advantage of this technique is that the tissue is living and functions as a whole tissue
50
In what conditions is endothelial dysfunction present in?
Age
Smokers
Diabetic patientds
High cholesterol diet
51
What are the 3 layers of the vascular wall?
Externa/ adventitia= connects artery to. surrounding tissues. Lots of collagen to prevent expansion
Media= smooth muscle and elastic fibres (elastin) Intima= layer of endothelial cells on a basement membrane (monolayer)
52
Why are endothelial cells heterogenous?
Endothelial cell phenotypes vary between different organs, between different segments of the vascular loop within the same organ, and between neighbouring endothelial cells of the same organ and blood vessel type.
Have different protein expression
When ECs are removed from their native tissue and grown in tissue culture, they become uncoupled from critical extracellular cues and undergo phenotypic drift
For this reason, studies of cultured endothelial cells are fraught with limitations.
However some properties are epigenticially fixed- 50% of the vascular bed specific genes from tonsils were 'washed out' when cultured in vitro.
There is a role for both tissue environment and epigentics in mediating differential gene expression
53
What is oxidative stress?
It is a situation associated with the excessive build up of free radicals (molecules containing an unpaired electron in its outmost shell) and molecules that cause unwanted oxidation of other molecules.
A common free radical is superoxide O2-
54
What are effects of oxidative stress?
Tissue damage
Necrosis and apoptosis
DNA damage
Inflammation
Lipid oxidation
Altered cell proliferation
55
How does oxidative stress cause CVD?
Involved in atherosclerosis, stroke, diabetes, hypertension and MI.
When LDL gets oxidised, it is much easier to take up into arterial wall.
NO reacts with superoxidide but this leaves less NO (NO half life depends on the amount of superoxide)
56
What can cause oxidative stress?
- Cellular respiration (Converting ATP-ADP, need a free radical reaction through the electron transport chain)
- Aging
- Inflammation (macrophages engulf pathogens, kill them via lysosomes which produce free radicals to kill the pathogen)
- Disease
- Drugs e.g. alcohol, paracetamol
- Smoking
- Radiation
57
What is an anti-oxidant and what are examples?
A molecule that prevents or reverses oxidation reactions of other molecules
Vitamin C (ascorbic acid), vitamin E, ubiquinol, glutathione
58
Does improving antioxidant levels prevent CVD?
Large trials such as the HOPE trial showed no significant improvements in CVD outcome from vit E
Other trials also show no benefit- ATBC, and GISSI
A few studies show improvements- CHAOS
59
What are the problems with anti-oxidant studies?
- Improvements in endothelial function does not necessarily translate to mortality reduction
- Confounding factors- dietary factors, health of participants, smoking, polypharmacy
- Negative results from smaller studies less likely to be published
- May need higher doses of anti-oxidants
- Treatment may not have been started early enough
60
What functions does the endothelium have?
Endothelium has a wide variety of roles including the regulation of vasculartone, modulation of inflammation, and promotion or inhibition of vascular growth and of platelet aggregation and coagulation.
61
What is the kindling radical concept?
Levels of BH4 seem to play a role on eNOS dependent ROS production
in the absence of this coenzyme, NOS reduces molecular oxygen rather than L -arginine, resulting in the production of superoxide rather than NO, a phenomenon known as ‘NOS uncoupling’
The superoxides produced will oxidise BH4 to BH3 and lead to further ROS formation- process known as kindling radicals
62
How do statins help endothelial dysfunction?
Preclinical studies show treatment of diabetic or hypercholesterolaemic animals with statins is able to prevent NOS uncoupling
It can do this via preventing BH4 oxidation
Leads to an increase in endothelial function
63
What are the discrepancies between trials oxidative stress?
Large discrepancy between cohort studies and RCTs
Cohort studies show higher intake of Vit C/E or anti-oxidant rich food
RCTs have failed to demonstrate a beneficial effect of supplements on cardiovascular morbidity and morality
May be biases in the cohort groups or trials may have started anti-oxidant therapy too late
64
What are reasons for the fail of anti-oxidant therapy in humans?
Vitamin E and other used antioxidants can be oxidized within the organism and thus acquire toxic properties instead of beneficial effects, and the properties of their constituents, should be taken into account.
- Also, the period of the antioxidant use can be too short for the beneficial effect to be observed.
- Another possible reason is the insufficiency of only one used antioxidant, or, in contrast, an additional antioxidant effect can be unnoticeable on the background of the use of statins, aspirin, and other cardioprotective drugs, which exhibit an antioxidant effect on their own
65
What is the most important antiatherogenic defense principle in the vasculature?
NO is also involved in the inhibition of platelet aggregation and adhesion and also suppresses key processes in vascular lesion formation
66
What enzyme has been identified to have a key role in atherosclerosis?
NAPDH Oxidase NOX
Inactivates NO
NOX deficiency in rats produced reductions in atheroscelotic plaque formation
67
How are ROS involved in heart failure?
ROS stimulate myocardial growth, matrix remodelling, cellular dysfunction by activating transcription factors and signalling kinases
ROS also affect the ECM, stimulating the proliferation of cardiac fibroblasts and activating MMPs (matrix metallopriteinases), fundamental effects leading to fibrosis and matrix remodeling
NOX also
68
Which drugs are involved in decreasing ROS production?
Some common antihypertensive medication, such as Ang 1 receptor blockers and angiotensin-converting enzyme (ACE) inhibitors, have been shown to exert their antihypertensive action in part by inhibiting NADPH oxidase and decreasing ROS production
69
What is the adhesion cascade involved in the formation of atherosclerosis?
Adhesion cascade= the rolling, tethering, adherance and migration of leukocytes through the endothelium
Mediated by adhesion molecules such as vascular cell adhesion molecule-1
70
What is evidence that hypertension contributes to atherosclerosis?
Leukocyte adhesion rates were higher in a rat carotid artery in a vessel chamber at higher blood pressures
71
What is the likelihood of approval rate for CVD clinical trials?
8.7% for phase I
Lower compared with other clinical fields
72
What is atherosclerosis?
A slow and silent progressing pathological process involving the intima and media of large and medium sized arteries which leads to the formation of focal lesions (plaques) containing lipid material and fibrous tissue
Mainly found at branches and junctions (shear stress at points in disrupted flow contributes to formation)
73
What are preclinical models of atherosclerosis?
Both APOE -/- and LDLR -/- mice develop atherosclerosis in a normal diet
However these mice do no die from atheroscleosis so may not be the best preclinical model.
Also have an accelerated mode of disease progression over months, whereas in life, the disease progresses over many decades.
Gain-of-function proprotein convertase subtilisin/kexin type 9 (PCSK9) mutants can also be used (insert recombinant adenoids-associated virus with gain of function forms of PCSK9)
74
What are the different treatment methods of atherosclerosis?
Lifestyle factors
Medical interventions- thrombolysis (clot busters)
Anti-platelet therapy- aspirin and clopidogrel
ACEi, B-blockers, CCBs- decrease bp
Lipid lowering agents
75
What are examples of lipid lowering agents?
Statins
PCSK9
Ezetimide (stops cholesterol absorption from gut)
76
What are the pros and cons of statins?
1/4 of people on statins do not achieve normal lipid levels
Also can have side effects such as muscle pain, rhabomydosis and tiredness
Statins have pleiotrophic effects
77
What are the pleiotrophic effects of statins?
Anti-oxidant properties
Anti-inflammatory
Anti-thrombotic
Improved endothelial function
Angiogenesis
Plaque stability
78
What were the ORION-10 and 11 trials?
Looking at inclisiran, a small interfering RNA
Found injection given s.c. every 6 months reduced LDL levels by ~50%
Only mild adverse effects
79
What is an example of a anti-inflammatory treatment that has been successful in treating CVD?
COLCOT trial- tested colchinine (treats pericarditis). Found a 23% reduction in the development of acute coronary syndromes
Longitudinal cohort studies in RA patients have shown a reduction in CVD events with the use of methotrexate, with a 28% relative reduction in total CVD events and a 19% reduction in myocardial infarction (MI).
It remains unclear whether these effects are directly related to the reduction of circulating inflammatory cytokines or if other off-target effects are involved (methoxtrexate may impact cholesterol transport)
80
How do NSAIDs work?
NSAIDs block a specific enzyme called cyclooxygenase (or COX) used by the body to make prostaglandins.
81
Why are inflammation and CVD thought to be linked?
Rheumatic diseases, such as RA, are associated with elevated levels of inflammatory cytokines
Individuals with these diseases have a higher risk of CV events and imaging studies confirm a greater burden of atherosclerosis
In KO mice of specific inflammatory cytokines, such as IL-1, TNF and IL-17, there is a significant reduction in the burden of atheroscleorsis
82
Are statin benefits exhibited in patients who have normal cholesterol levels?
Yes
83
What non-lipid benefits do statins have and what is the proof for this?
Treatment of cultured vascular ECs with pravastatin, simvastatin, fluvastatin and cerivstatin reduces the synthesis of the proinflammatory cytokines
Endothelium-dependent flow- mediated dilatation was significantly improved by cerivastatin in the absence of any change in the lipid profiles in patients
84
What are the different types of anticoagulant drugs?
Heparins
Vitamine K antagonists
Direct oral anti-coagulants
85
How do heparins work?
Heparins enhance the activity of antithrombin, which inhibits blood clotting factors
Unfractionated heparin= used for immediate anticoagulation in emergency situations
Low molecular weight heparin= used for long term anticoagulation
86
What is an example of a vitamin K antagonist?
Warfarin
It interferes with the production of vitamin K dependent clotting factors in the liver
Patients taking warfarin need regular blood tests to ensure their blood clotting time is within the therapeutic range
87
What are examples of DOACs and what do they target?
Direct oral anticoagulant drugs
Dabigatran= inhibits thrombin
Rivaroxaban, apixaban, edoxaban= inhibits factor Xa
88
What are common anti-platelet drugs and how do they act?
Aspirin= inhibits the activity of COX, reducing the producting of thromboxane A2, a substance that promotes platelet aggregation
Clopidogrel, Prasugrel, Ticagrelor: These drugs inhibit the activation of platelets by blocking specific receptors, preventing them from binding to each other.
89
What is thrombosis, what can cause it and what can it lead to?
Innapropriate platelet activation and coagulation
Clotmade of platelets and fibrin
Conditions such as athersclerosis, smoking, hypertension, diabetes and high lipid levels are risk factors
Deep vein thrombosis can lead to pulmonary embolism or DVT.
Arterial can lead to stroke or heart attack
90
What is the coagulation cascade?
- The intrinsic pathway is activated by trauma inside the vascular system.
- The external pathway is activated by external trauma that causes blood to escape from the vascular system.
- The intrinsic and extrinsic pathways converge into the common pathway.
- Factor X is activated by either pathway, leading to the formation of thrombin.
- Thrombin is a key enzyme that converts fibrinogen into fibrin, which forms a mesh that stabilizes the blood clot.
91
What is fibrinolysis?
The process of breaking down a clot
92
What causes platelet activation?
Damage/rupture of blood vessels causes collagen exposure and release of pro-aggregants
This leads to platelet activation
This activation causes adhesion and aggregation to form clumps, de-granulation (release of pro-aggregants in a feedback loop) and initiation of coagulation cascade
93
What are the sides effects of aspirin?
GI side effects such as peptic ulcer bleeds
The acidic environment causes aspirin to remain nonionized, forcing it to accumulate in gastric mucosal cells, which alters the permeability of the cell and causes ulceration.
94
What is the DAPT score?
The DAPT score was derived from a large scale clinical trial called the DAPT study
The DAPT score incorporates several clinical and demographic factors to estimate an individual patient's risk and potential benefits from extended dual antiplatelet therapy. These factors may include age, history of myocardial infarction or stent thrombosis, history of bleeding, and others.
95
How are genotypes going to be used in the future to guide anti-platelet therapy?
Clopidogrel can be more effective with less risk of bleeding than ticagrelor in patients without CYP2C19 mutations that impair conversion of prodrug to active drug
Clopidogrel= ADP receptor blocker
Ticagrelor= P2Y12 receptor antagonist
96
What is the pathway that leads to activation of platelets?
97
Does dual-antiplatelet therapy successfully reduce CV events?
Despite treatment with dual-antiplatelet therapy, patients with stabilized ACS have an ≈9% to 11% risk of suffering a recurrent adverse cardiovascular event within 1 year.
98
What is useful with DOACs?
There is an antidote- can reverse their actions and stop severe bleeding
99
What anti-thrombotic drugs are used most often?
DOACS- $17.2 billion
100
Should anti-thrombotic drugs be combined with anti-platelet drugs?
2017 trial- rivaroxaban with or without aspirin in CVD
28K patients from > 500 centres, no prior MI or stroke
Rivaroxaban plus aspirin better than aspirin alone
Significant increase in bleeding risk, not fatal, but deaths reduced by 23%. This was a useful balance as benefit outweighed harm
101
What is the gold standard for treatment of ACS?
Dual anti-platelet therapy consisting of aspirin with a P2Y12 inhibitor
102
What anti-thrombotic drug achieves instant anti-platelet inhibition?
Cangrelor
An intravenous, reversibly binding platelet P2Y12 receptor antagonist,
Has near complete inhibition of ADP-induced platelet aggregation within 2 min after bolus injection
Found to be effective in reducing death and MI
103
What is cheaper DOACs or warfarin?
Warfarin is much cheaper than NOACs: average monthly supplies are $20 for warfarin and $350 for NOACs
104
What is hypertension?
Systolic blood pressure of 140mmHg or more, or a diastolic blood pressure of 90 mmHg or more, or taking hypertensive medications
105
What are the consequences of hypertension?
Stroke (both types) and dementia
Retinopathies, blindness
Atherosclerosis
Heart muscle hypertrophy
Risk of MI increased
CKD
105
What is the SHEP trial?
- The trial aimed to determine whether treating isolated systolic hypertension in elderly individuals (> 60 years) would reduce the incidence of stroke and other cardiovascular events.
- The active treatment group received antihypertensive medication, specifically a low-dose diuretic (chlorthalidone), the placebo group recieved inactive pills
- Managed to decrease blood pressure by 15 mmHg in treatment group
- Antihypertensive medication in older individuals with isolated systolic hypertension ignificantly reduced the risk of stroke, heart failure and other CVD.
106
What was the ALLHAT trial?
To determine what type of anti-hypertensive medication was most effective in preventing CVD
42,000 participants were given either:
- Thiazide type diuretic
- Calcium channel blocker
- ACEi
- Alpha blocker
The trial found that thiazide-type diuretics were superior to other hypertensive medications
107
What was the SPRINT trial?
Subjects assigned to intensive blood pressure lowering (<120 systolic) or standard treatment (<140 systolic).
The SPRINT trial found that the intensive blood pressure control group, targeting a systolic blood pressure of less than 120 mm Hg, had a lower rate of cardiovascular events compared to the standard treatment group. The trial also showed a lower rate of all-cause mortality in the intensive treatment group.
108
What is an example of a RNA interference molecule targeting angiotensinogen?
ALN-AGT
Blocks angiotensinogen production for many months
Drug currently in phase II trials
Blood pressure reduction in week 8 and 12
Most common was adverse effect was reaction at injection site
Now called Zilebiseran
KARDIA trials
109
What is the therapy routes for hypertension?
A= ACEi, C= Calcium channel blocker, D= thiazide diuretics
- ABEi First line therapy for people <55 year-olds
- CCBs first line therapy for people >55 years-old and black people of African or Caribbean origin of any age (may not be true now)
- TDs given in those where CCB is not suitable i.e. significant heart failure, oedema
110
What are side effects of common anti-hypertensive drugs?
ACEi= 10% of patients get a cough, AKI
CCBs= headaches, ankle swelling, also Gingival hyperplasia (overgrowth of gums) can lead to teeth loss
- Thiazides- impotence, rashes, diabetes, gout
111
What are beta-blockers indicated for?
- Now no longer thought of as first line agent for hypertension due to diabetes risk and poor outcome data
- Still useful though in patients with ischaemic heart disease (anti- anginal) and heart failure as well as a rate limiting agent in those with arrhythmias
- Also occasionally useful in the young who don’t tolerate ACE-I or ARB
112
What is the incidence of hypertension and hypertension-related deaths?
The global prevalence of hypertension was estimated to be 1.13 billion in 2015
Accounted for almost 10 million deaths- leading global contributor to premature death.
113
What is the RAAS and what drugd act on it?
Renin-angiotensin- aldosterone system
ACEi- angiotensin converting enzyme inhibitor. Stops angiotensin I from becoming II
ARBs- angiotensin receptor blocker. Blocks angiotensin II from binding to its receptor
114
How do beta-blockers cause diabetes?
Inhibition of insulin release can lead to hyperglycemia, and beta-blockers have long been considered to inhibit insulin release through pancreatic beta-receptor blockade
115
What is PET imaging?
- Positron emission tomography
- Provides information on a specific biological or biochemical process in the living body by in vivo quantitative measurement of a radiotracer.
- Combines a compound of interest with a radioisotope so it can be tracked.
- PET scanner detect gamma-ray photons emitted by positrons. The collected data is used to reconstruct 3D images
116
How is PET used in drug development and research?
Can label a drug to see where it binds
Can be used to evaluate the best drug dosage for clinical use
117
What can PET can used for now in CVD?
New glycoprotein IIb/ IIIa receptor radiotracer 18F-GP1 can be used to detect venous and arterial thrombi. Currently being investigated in a human clinical study
Tracers being developed for inflammation, and fibrosis
118
What is heart failure?
When the heart muscle can't pump enough blood to meet the body’s needs for blood and oxygen
Main causes are myocardial infarction, hypertension or cardiomyopathy
Symptoms include fainting, lightheadedness, lethary, persistant cough, shortness of breath, oedema
119
How well can the human heart regenerate?
Zebrafish have a robust capacity for myocardial regeneration
Mice hearts can regenerate upto 7 days after birth
Adult hearts have a low capacity for regeneration.
Cardiomyocyte renewal in the human heart shown using carbon dating, however, this is inadequate to replace cardiomyocytes after MI
120
What are the stats for heart failure due to MI incidence?
Heart failure due to MI affects over 38 million patients worldwide, in the UK alone >0.5 million people living with heart failure
121
What is the multi-phase injury response to MI in the adult human heart?
- Maassive influx of inflammatory cells to remove dead tissue
- M1 macrophages secrete pro inflammatory mediators and M2 secrete reconstructive molecules
Collagen type 3 placed down and a scar is formed. Then replaced by type 1. Still forms a scar and is never regenerated
122
What animal can regenerate its heart?
Zebrafish- cut off 20% of its heart and it can regenerate it within 3 months
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How does cardiac regeneration occur in zebrafish?
Regeneration occurs by cardiomyocyte dedifferenetiation and proliferations (then they redifferentiate back)
Discovered by using transgenic strained cells and lineage tracing with Cre-Lox A
Also there is a role of the epicardium (thin layer covering the hearts surface). Secrete factors that cause other cells to differentiate and can also contribute to different cell types
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How is RNA sequence been used to understand cardiac regeneration better?
RNA seq done on zebrafish (cardiac regenerates) and medaka fish (does not regenerate)
Found differences in immune responses- neutrophil response never gets resolved in medaka fish, unlike zebrafish
Also there is never a wave of macrophages infiltration in tge medaka. Injection of a immunstimulant increased macrophage infiltration and cardiomyocyte proliferation in the injured medaka heart
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What is comparitive transcriptomics?
A field of study hat involves comparing the transcriptomes of different biological samples to identify differences in gene expression. The transcriptome refers to the complete set of RNA molecules, including messenger RNA (mRNA), in a cell or a population of cells at a specific point in time.
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What is a GWAS?
Genome-wide association study
Used to identify associations between specific genetic variations (single nucleotide polymorphisms or SNPs) and particular traits or diseases across the entire genome.
Genotype all individuals and getting mutations that link to certain traits.
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How can you look at many different mutations and how they effect functioning in zebrafish?
Large scale, droplet based CRISPR mutagenesis in zebrafish
Droplets targeting hundreds to thousands of different genes are intermixed together and barcoded and injected into zebrafish embryos from a single needle.
The fish end up with a random mutation
Embryos are raised en masse, and then those exhibiting the phenotype(s) of interest are isolated and the identities of the perturbed genes are rapidly uncovered by retrieving and sequencing the barcodes.
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Why are zebrafish well suited to CV studies?
high similarity between human and zebrafish cardiac action potentials
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Why might epicardiods be useful in the future>
Epicardioids mimic the multicellular pathogenesis of congenital or stress-induced hypertrophy and fibrotic remodeling. As such, epicardioids offer a unique testing ground of epicardial activity in heart development, disease and regeneration.
Epicardioids mimic left ventricular hypertrophy (LVH) and fibrosis when treated with endothelin-1, a potent vasooconstrictor known to induce hypertrophy
Epicardiods could be exploited for preclinical testing to identify drugs that could be used to target heart failure.
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What is cardiac fibrosis and what does it cause?
Dysregulation between the synthesis and degradation of extracellular matrix proteins or ECM (e.g. collagen, matrix metalloproteinases), leading to a accumulation of ECM in the myocardium
Interstitial fibrosis is where ECM starts to accumulate between cardiomyocytes
Replacement fibrosis covers a gap created in the cardiomyocytes after injury
Fibrosis causes increased stiffness, impaired contractibility, heart rhythm dysregulation and abnormal myocardial perfusion
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What molecules can activate myofibroblasts?
Angiotensin II and TGF beta can induce activation of fibroblasts into myofibroblasts
Fibroblasts migrate from around the heart in response to injury and differentiate to myofibroblasts and these are better at excreting ECM
Also adrenergic stimulation actives fibroblasts
Inflammatory cytokines, chemokines, and growth factors have been implicated in the pathogenesis of cardiac fibrosis
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What is a potential contributer to fibrosis and a potential therapeutic?
Increased primary cilia (microtubule based structures that protrude from the surface of many cells in the human body)
Increased primary cilia in idiopathic pulmonary fibrosis
KO of ciliary proteins in vitro using siRNA. When polycystin 1 is removed collagen does not go up in mice
Therefore, pharmacological blockade of these proteins may help stop cardiac fibrosis
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What drugs partially decrease the development of fibrosis?
Treatments for HF that have shown efficacy such as angiotensin converting enzyme (ACE) inhibitors, AngII receptor blockers (ARBs), and mineralocorticoid receptor antagonists have shown that their therapeutic effects are in part due to their ability to decrease the development of fibrosis. However, no therapeutic intervention directly targets the fibrotic response
Experimental studies have suggested that several additional anti-fibrotic interventions may hold therapeutic promise, including inhibition of fibrogenic pro-inflammatory cytokines (such as IL-1 and CCL2)
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What are the pros and cons of PET scans?
Only sub-pharmacological doses of the radiotracer are required so it does not impact the molecular process being studied.
- Also can track changes in real time- pharmacokinetics of a drug can be studied
- However, the radiation dose limits the type of patients that can targeted with the scans- e.g. paediatrics although radiation dose is decreasing
- Also, whilst the sensitivity is high, the resolution is low
- It also requires complex infrastructure and expertise
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What is the most common PET radiotracer?
[18F]FDG is a radioactive glucose analogue that is used as a tracer in PET imaging
- Glucose is a primary source of energy for cells, and FDG is taken up by cells in a manner similar to glucose.
- Taken up by GLUT1 (higher metabolism= higher number of them). Reflective of glucose metabolism
~90% of PET studies use this
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How are PET scans used in cardiology?
Can assess perfusion using [15O]H2O which may be valuable as a prognostic marker
Can also use it to assess whether a drug is efficient (does the drug help with perfusion)
FDG is used to evaluate myocardial viability.
Can combine both perfusion [15O]H2O and viability [18F]FDG to see what areas of tissue may be rescued.
However, large clinical trials found that imaging of myocardial viability failed to deliver effective guidance of coronary bypass surgery to reduce adverse cardiac outcomes
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How is PET imaging able to quantify inflammation in cardiology?
Inflammation is associated with an increase in glucose metabolism, primarily due to the activation of immune cells such as macrophages and neutrophils. These cells require energy to carry out their functions, such as phagocytosis and cytokine production. [18F]FDG, being a glucose analog, accumulates in these metabolically active cells (especially in M1 macrophages). However, this method requires supression of cardiomyocyte glucose metabolism (fasting and heparin are required)
Can also track TPSO for inflammation (expressed on outer membrane on mitochondria and is highly expressed by macrophages). 18F-LW223 by UoE was found to accurately map macrophage-driven inflammation in rodents
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What is pseudo-theragnostics?
Where imaging target overlaps with the therapeutic target, allowimg patient risk stratification, patient selection for precise therapy and refinement of dosing and timing of such compound
In the future PET/CT may be a central contributor to precision medicine
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Why is heart failure clinically important?
1 in every 100 people will get heart failure
It is expected to rise in the next 20 years due to aging population, successful management of MI
£2.4billion per year or 2% of NHS budget
Causes 5% of all hospital admissions
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What is the acute clinical management of chronic heart failure?
Need to reduce preload- i.v. diuretic e.g. furosemide and NO donors such as glyceryl trinitrate
Inhibits salt reuptake back from the urine into the body- inhibits Na+/K+ cotransporters
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What are positive inotropes?
Increase strength of myocardial contraction via beta agonist effects
Leads to increased ejection of blood from the heart during each contraction
Include levostimendan, adrenalin, milrinone and dopamine
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What was the PROMISE study?
Looked at milrinone
Increases intracellular levels of cyclic AMP
As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes
Disaster for milrinone and positive inotropes
Caused arrythmias
However levostimendan increases contracibility, but does not increase Ca2+. Has favourabe outcomes
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What is the chronic management of heart failure?
Diuretics- furosemide
ACEi, ARBs and spirnolactone to counteract RAAS
Aldosterone synthase inhibitors are undergoing clinical development
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What is spirnolactone?
Aldosterone antagonist
RALES study- demonstrated a significant reduction in both all-cause mortality and hospitalization for heart failure in the group receiving spironolactone compared to the placebo group.
Survival increased at sub-diuretic doses
Gynecomastia was reported in 10% of men
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How do SGLT2 inhibitors work?
SGLT2 inhibitors block sodium and glucose co-transporter
Helpful as causes diuresis and lowered glucose levels
Empaglifozin is an example- 38% relative risk reduction of CV death.
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How do SGLT2 inhibitors exert their effect?
SCLT2 inhibition is benefical in non-diabetic cardiac disease
- Cardiac cell metabolism is the leading effect at the moment- cardiac cells think they are entering a starvation state and so switch from carb metabolism to ketone metabolism which is far more efficient at oxygen metabolism.
- SGLT2 inhibitors have been associated with improvements in arterial stiffness
- SGLT2 inhibitors may improve endothelial function, leading to better vasodilation and reduced vascular resistance.
- SGLT2 inhibitors have been associated with improvements in metabolic parameters, including reductions in body weight and visceral adiposity.
- Some studies suggest that SGLT2 inhibitors may have anti-inflammatory effects, leading to a reduction in systemic inflammation
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What trial tested SGLT2 inhibitors?
EMPA-REG trial- 38% relative risk reduction of CV death, 32% of all cause mortality and 35% of hospitalisation for heart failure
Did increase the risk of genital infection however
A meta analysis of two other trials; EMPEROR-reduced and DAPA-HF trials found there was a 25% reduction in CV death and hospitalisation in non-diabetic patients
