heart failure Flashcards
heart failure is a failure of — function recognized by a characteristic pattern of responses:
- —
- —-
- —
- —
The initial adaptive mechanisms that work in the short term cause problems in the long term.
The adaptive mechanisms include — cardiac — , myocardial — and activation of — mechanisms
HF can be — or —
Acute decompensated heart failure (ADHF) is an acute — of HF — and a common — department presentation
- A diagnosis of heart failure requires— symptoms
pump
haemodyamic
renal
neaural
hormonal
intrinsic cardiac compression
myocardial hypertrophy
neurohumoral
acute or chronic
acute worsening
symptoms
emergency
clinical
Heart failure - left sided:
Left side of heart pumps blood around the — , the — powerful side of the heart
Heart failure with reduced ejection fraction (HFrEF), also called — failure:
The left ventricle loses its ability to — normally. The heart can’t pump with enough – to push enough blood into circulation.
Heart failure with preserved ejection fraction (HFpEF), also called — failure (or—- ):
The left ventricle loses its ability to – normally (because the muscle has become —). The heart can’t properly – with blood during the — period between each beat.
body
most
systolic
contract
force
diastolic failure
diastolic dysfunction
relax
stiff
fill
resting
Heart failure – right sided:
Right ventricle pumps blood to the —
Right-sided or right ventricular (RV) heart failure usually occurs as a result of — failure.
When left ventricle fails, increased — pressure damages the heart’s right side.
Right side failure, causes blood to back up in the–.
Causes — in the legs, ankles and the abdomen such as the GI tract and liver (causing— ).
( info:
1- The decline in ejection fraction is continuous. Normal and low are arbitrary definitions
2- As EF is not reduced, HFpEF is difficult to diagnose. H2FPEP is an easy to use diagnostic tool
)
lungs
left sided failure
increased fluid pressure
veins
swelling
ascites
physiology and drugs:
Preload : —-
Afterload : —-
Contractility : —
Systemic Vascular Resistance : —
diuretics
vasodilators
inotropes
vasodilators
SGLT-2 inhibitors:
SGLT-2 inhibitors reduce uptake of —
Proven to be effective in managing —
Dapagliflozin and empagliflozin have been proven to be effective in HF
Benefit is — of — control
Mechanism of benefit in HF is unclear and probably involves:
-osmotic diuresis and natriuresis,
- — interstitial fluid volume and blood pressure,
-improve — function,
-ameliorate LV —
-prevent —
glucose
diabetes
independent
glycaemic
decreases
LV function
remodelling
arterial arrhythmia
nitric oxide:
NO* is a – and is different from nitrous oxide the –
NO* is a — and is therefore — with a — half-life
NO can be produced – or –
— are source of NO
NO is synthesised in — cells
NO diffuses from – cells to — cells
Potent –
- nitric oxide production :
– subunit is responsible for activation nitric oxide synthase (NOS)
Produced by during conversion of — to —
gas
anaesthetic
free radical
unstable
short
enzymatically or chemically
nitrates
endothelial cells
endothelial cells to smooth muscle
vasodilators
Gb
arginine to citrulline
NO activates —- :
- Guanylate cyclase (GC) converts – to –
- Can be —linked or —
- Soluble GC is activated by —
- cGMP activates —
- — is important in smooth muscle cell relaxation
- cGMP is metabolised by — to —
- GC , PKG pathway important – target in HF
–> Activators of –
–> Inhibitors of –
Act to correct the — dysfunction found in HF
soluble guanylate cyclase
GTP to cGMP
receptor or soluble
NO
protein kinase G
PKG
phosphodiesterase (PDE) to GMP
drug target
GC
PDE
endothelial
NO donors:
NO donors are — that act by — NO
These include the classic —- :
amyl nitrite,
glyceryl trinitrate,
isosorbide dinitrate
sodium nitroprusside
Mechanism of NO release is unknown but is enhanced by — and —
Tolerance to nitrates develops requiring nitrate — periods
Tolerance can be due to increased — production
Nitrate treatment also leads to — of PDE1A1 in SMC
compounds
releasing
nitro vasodilators
cystein and glutathione
free
superoxide
upregu;ation
1- Vericiguat is a — of soluble GC
It is an — activator that enhance NO — and also a direct activator of —
Approved for use in HF
2- phosphodiesterase:
Phosphodiesterase (PDE) breaks down – and—
PDEs are —
There are – PDE’s
PDE 4, 7 & 8 are specific for –
PDE 5, 6 & 9 are specific for –
PDE 1, 2, 3, 10 & 11 are –
PDE inhibitors:
— is a selective PDE5 inhibitor approved in 1998 for — dysfunction (Viagra) and for — (Revatio)
Milrinone and amrinone are — inhibitors.
Increase — levels in myocardium
— ionotropes
Used in — decompensated HF
direct activator
allosteric
binding
GC
cGMP and cAMP
dimeric
11
cAMP
cGMP
non specific
sildenafil
erectile dysfunction and pulmonary hypertension
PDE3
cAMP
positive
acute
Hydralazine:
Direct —
Mechanism of action unclear
Possibly inhibition of —mediated – release
inhibition of — in — cells
Used in conjunction with — (isosorbide dinitrate) in HF
Ivabradine:
Blocks the — channel in cardiac –
— heart rate increasing — time
Approved for use in HF
arterial vasodilator
IP3
ca
myosin phosphorylation
arterial smooth muscle
nitrate
If
cardiac pacemakers
slows
filling
info: check slide 35
A. The sinoatrial node (SAN) is the primary place of action on cardiac tissue. B. Ivabradine blocks the intracellular aspect of the hyperpolarization-activated cyclic nucleotide-gated transmembrane channel which is responsible, in the open state, for the transport of sodium and potassium ions across the cell membrane. This leads to inhibition of the funny current (Iƒ) channel, which is specifically activated at hyperpolarized membrane potentials. C. Ivabradine causes a dose-dependent reduction in heart rate via the mediated slowing of diastolic depolarization (shaded region) and increasing the duration of diastole without altering other phases of the action potential
1- Inotropes are agents that act to enhance the — of the heart
Often associated with — that alter the – balance in myocytes
Positive inotropes used in the — term treatment of —
–> — inhibitors
–> — agonists
2- beta blockers:
Increased — activity in HF
— cardiotoxicity
Imbalance of myocardial — supply/demand
— overload,
Increased oxidative stress
Coronary spasm
Depletion of energy stores
Increased mitochondrial permeability
Clinical consequences include:
reduced — function
Reduced left ventricular — ,
acceleration of the left ventricular — process,
- —
Some beta blockers are approved for HF
Bisoprolol
Carvedilol
Metoprolol
Nebivolol
- beta blocker CONTRAINDICTION :
- 11-11 degree AV block ( cardiological)
- critical limb ishcmeia ( non cardio)
- recent exacerbation of HF ( cardiological)
- severe asthma , or severe COPD ( non cardio)
contractility
drugs
ca+2
short
heart failure
Phosphodiesterase inhibitors
Beta1 adrenoreceptor agonists
sympathetic
catecholamine
oxygen
calcium
systolic function
ejection fraction
remodelling
ventricular arrhythmias
Heart Failure and Beta Blocker Paradox:
b1 receptor in the — .
Increased — and rate of — .
Increase conduction — .
b2 receptor in — mediates — .
b-blockers are used in the treatment of —
Over stimulation of b-receptors during HF lead to — and reduced —
b-blockers restore sensitivity of—
heart
force and rate of contraction
velocity
smooth muscle
relaxation
heart failure
de-sensetixation
reduced signalling
adrenoreceptor
Heart Failure and Diuresis:
Heart failure is characterised by — overload and often —
Thus, drugs that promote diuresis are essential in HF
These drugs act to promote — in the —
Agents include:
- —
- —
- — inhibitors
- — receptor antagonists
fluid
oedema
na+ excretion in kidney
diuretics
ACE inhibitors
neprlysin
Mineralocorticoid
1- aldosterone: — hormone , —
Promotes —
Increases —
Acts on —-
Antagonists include:
-Spironolactone
-Eplerenone
Increase — levels in esp in — disease
Non-steroid antagonists:
Apararenone
Finerenone
Esaxerenone
2- Natriuretic peptides :
A family of peptides that increase —
— (ANP)
— (BNP)
— (CNP)
They act by binding to — receptors
NPR-A, -B & -C
BNP not effective in – but used as a – tool
steroid hormone m mineralocorticoid
na reabsorption
mineralocorticoid receptor
k+ levels
chronic kidney disease
na excretion
atrial
brain
c type
specific
HF
diagnostic
neprilysin:
Neprilysin is a—
Inactivates — :
Enkephalins
Bradykinin
Oxytocin
Natriuretic peptides!!!
Sacubitril is a —, — of neprilysin
Increases levels of — peptides such as – & —
Causes —
Used in combination with — receptor blocker
Sacubitril/valsartan
metalloprotease
peptides
pro drug inhibitor
vasoactive peptides
ANP , BNP
vasodilation
angiotensin receptor blocker
Loop Diuretics:
Act on thick — of —- ,
- inhibit — carrier,
- inhibit transport of — out of – ,
- increase — .
Given — and —
— onset
—- of total body Na+
Hypokalemia
hypomagnesemia & hypocalcemia
Ototoxicity,
Can cause hyperuricemia leading to gout
Hyperglycemia
Loop diuretics may increase —
ascending limb of loop of henle
na/k/cl carrier
NaCl
tubule
water excretion
oral and intraveously
rapid
depletion
LDL
Targeting Renin-Angiotensin-Aldosterone system in HF:
RAAS is important in regulation —
It leads to — of – which helps – fluid
Due to oedema in HF significant benefits in – RAAS
Angiotensin converting enzyme inhibitors:
Block — of Ang II
Angiotensin receptor blockers:
Block — of Ang II
Aldosterone antagonists:
Block —
fluid volume
re-absorption of Na
retain fluid
blocking
formation
actions
na resorption
1- Calcium Channel blockers in HF:
Conflicting results with Ca channel blockers in HF
Early studies showed no benefit or even worse outcome
Recent studies have shown benefit
Likely due to the different profiles of Ca-channel blockers
— such as amlodipine have better profiles for HF
2- direct cardiac myosin activation + inhibition :
The actin-myosin interaction is critical for the — of cardiac myocytes
This is an —-dependent process requiring —
—- specifically binds to the — domain of cardiac—
—- activation of myosin increases binding to actin
It—- ATP turnover in in the absence of actin
The result is an increase in the number of — heads that can bind to the — filament
This enhances cardiac —
Mavacamten is a cardiac — used in treatment of —
Dihydropyridnes
contraction
energy
ATP
Omecamtiv
catalytic domain
cardiac myosin
allosteric
reduces
myosin
actin
cardiac contraciltiy
myosin inhibitor
hypertrophic cardiomyopathy
Levosimendan:
Binds to cardiac —
Enhances the – to – without — the —-
It also causes — by opening — channels
troponin c
sensitivity
ca
increasing
ca concentration
vasodilator
opening k+
Digitalis:
Cardiac — initially described by Withering in 1775
It acts as a — inotrope
in the failing heart the Frank-Starling ventricular function curve is shifted — and to the— . Digoxin shifts this curve — and to the —
It has an effect on the — activity of the heart
slows — firing rate, and slows conduction through the — node
Cardiac slowing and reduced — of conduction
Increased — of contraction
Disturbances of rhythm:
Blockage of – conduction
Increased — pacemaker activity
Cardiac glycosides MOA:
Inhibition of — pump
Bind to – -subunit
Mechanism of increased — unclear but may be due to inhibition of — pump as well
This results in an — in intracellular Na+, — in cytoplasmic calcium due to decreased efflux of Ca++ through the — transporter
glycosides
positive
down and right
up and left
electrical activity
sa node
av
rate
foce
av conduction
ectopic pacemaker
Na/k+
alpha
bagel tone
na+/k+
increased
increased
Na+/Ca++ exchange
Digoxin adverse effects:
Digoxin has a — therapeutic index.
With regards to electrical activity, digoxin – can cause — electrical activity, i.e. — .
Other adverse effects include:
Gastrointestinal disturbance, nausea, vomiting, diarrhoea
CNS effects, include —-
— pharmacotherapeutic window, therefore measure — levels.
Toxicity exacerbated by— .
Toxicity may be treated in — situations with a specific — to digoxin
low
toxicity
disordered
arrhythmias
visual hallucination
narrow
plasma
hypokalaemia
life threatening
antibody
Pharmacotherapy in Heart Failure:
— for preserved and reduced EF are —
However, treatment is different for HFpEF and HFrEF
Little evidence of benefit of pharmacotherapy in –
— are used in HFpEF to reduce –
cut offs
arbitrary
HFpEF
diuretics
oedema
Managing HFrEF:
1- Patients will typically be on multiple agents
ACE inhibitors
Beta-blockers
Mineralocorticoid receptor antagonists
SGLT inhibitors
Loop diuretics
2-Patients are likely to have underlying conditions
Myocardial infarction
Hypertension
Diabetes
3-Patients need to continue treatment of these underlying conditions
info:
Heart Failure with preserved ejection fraction (HFpEF)
“…..Until recently, most pharmacological intervention trials for HFpEF yielded neutral primary outcomes. In contrast, trials of exercise-based interventions have consistently demonstrated large, significant, clinically meaningful improvements in symptoms, objectively determined exercise capacity, and usually quality of life……”
GLP-1 and HFrEF:
Semaglutide (GLP-1 agonist) shown to improve HFrEF in — patients in small study (2023)
Tirzepatide, dual GIP/GLP-1 agonist showed significant benefit in obese patients with HFpEF (2025)
Benefit was seen in mortality, worsening of HF, 6-minute walk and over all health
Due to weight-loss?
obese
