ICL 5.10: Pathophysiology of the Failing Heart Flashcards
what can cause an insult to the myocardium?
- fluid overload
- ischemic heart disease
- tachyarrhythmias
- exposure to toxins
- pregnancy
- infiltration (amyloid or ARVD/C)
- non-infiltrative restriction (hypertrophy)
- inflammation
- pericardial disease
- hormone abnormality
- nutritional deficiency or overload
what is the big picture of what happens when there’s an insult to the heart?
insult to the heart –> decreased CO –> lower BP is perceived by the kidney –> RAAS activated –> water and Na+ retention and angiotensin II causes vasoconstriction
overall results in high BP! this increases cardiac congestion, R arterial pressure, central venous pressure which intern causes venous congestion in the kidney which increases hydrostatic pressures = kidney can’t filter toxins
the decreased GFR decreases which causes reactive fibrogenesis and RAAS is further activated
ANP and BNP are activated to try and fight this whole disaster by causing dilation
so ultimately you get a loss of renal function, decreased GFR, decrease in urine output and decreased water and Na+ output
this leads to wall stress in the heart because of all this extra volume that just got added and you get maladaptive hypertrophy and cardiac remodeling
what happens when increased blood volume causes wall stress?
- Frank-Starling is helpful initially
- maladaptive hypertrophy
- maladaptive cardiac remodeling
activation of the neurohormonal systems
4. stimulation of the SNS
- stimulation of RAAS
- increased ANP and BNP to try and dilate
what is the Frank Starling effect and its role in CHF??
when there’s an increase in EDV, you dilate the chambers and increase tension by increasing actin-myosin cross-bridging –> this increases stroke volume and allows you to end up with the same ESV
however, if you have a weakened myocardium in this same setting of increased EDV, there won’t be an increase in SV because the muscle is weak! so we have an increased ESV which sometimes goes backwards and results in hypotension and pulmonary congestion
in early heart failure, you have to increase preload to keep the same stroke volume because you can’t increase your contractility and that’s why your kidney is trying to help by increasing pressure
why does hypertrophy happen in CHF?
after heart failure begins, pressure or volume overload increases the mechanical work of the cardiomyoctes which creates wall stress –> this increases protein synthesis and the number of mitochondria
- pressure overload = new sarcomeres are formed in parallel to the long axis of the cardiomyocytes which expands the cross-sectional area of the cardiomyocytes and creates concentric hypertrophy = the whole heart thickens in the same degree = thickened ventricular wall without dilation
- volume overload = stimulates new sarcomas in a series in a row within existing sarcomeres which causes an eccentric hypertrophy = not the same thickness without = dilation of the ventricles
overall you get an increase in size and mass which increases the metabolic demands of the heart butttttt there’s no associated increase in capillary volume so there’s a supply and demand mismatch which increases the risk of ischemia even without CVD!!
what is the cardiac remodeling that happens during CHF?
- there’s a shift of gene expression and an up regulation of early response and fetal genes….you change to a fetal cardiac development
in the developing heart glucose and lactate are used to get ATP but in the adult heart we use fatty acids – so in CHF you go back to using glucose and ketone bodies for energy which leads to a transcriptional down regulation of fatty acid metabolism machinery
- cardiomyocyte apoptosis
- abnormalities of intracellular Ca+2 function (because you’re trying to get the heart to contract differently)
- intracellular cytoskeletal changes
- extracellular matrix deposition
what is the cardiac apoptosis that occurs during CHF?
apoptosis is stimulated by mechanical strain, adrenergic stimulation , angiotensin II and TNF
this causes altered genetic expression of surface receptors, contractile proteins, ion channels and catalytic enzymes
NADPH oxidase receptor changes cause the production of ROS!!! high levels of ROS in the mitochondria release cytochrome c which stresses the endoplasmic reticulum and more catalytic enzymes are released which leads to cell death
what is the extracellular matrix deposition that happens in CHF?
the oxidative stress on the cardiac fibroblasts decreases collagen synthesis and activation of fibroblast degradation
the end result is a bad interstitial fibrosis because our good fibroblasts aren’t working correctly; they’re being degraded!
this impedes systolic and diastolic function since they’re both active processes
what is the neuro-hormonal system?
SNS, RAAS, and ANP/BNP are all activated to get an increase in contractility and EF
there’s an overproduction of NE and angiotensin II directly in the myocardium which cause an autocrine & paracrine effect –> natriuretic peptides and TNF are also synthesized
NE selectively binds B1 > B2 or alpha1 adrenergic receptors
this leads to a relative loss of effect of the vasodilators like NO, ANP, BNP, PGE2, PGEI2, and kinins!
why is there peripheral edema with CHF?
there’s a decrease in CO because your myocardium has been injured in some way so your SNS, RAAS, and ADH all kick in to try and increase pressure and blood volume
this causes a temporary increase in HR and contractility and vasoconstriction which initially maintains BP but eventually there’s a decrease in CO because ultimately the myocardium is too injured to keep up
the increased vasoconstriction in the veins increases preload because your body thinks maybe it’s a preload problem but you just end up backing up because your heart can’t contract normally which leads to peripheral edema and pulmonary congestion
how is the neurohormonal system activated via the SNS during CHF?
B1 mediated activity that initially increases contractility (inotropic) and HR (chronotropic)
this is ultimately maladaptive and contributes to hypertrophy, fibroblast hyperplasia, fetal gene induction, myocyte apoptosis and proarrhythmia
how does the brian play a role in CHF?
in a normal heart, there’s a parasympathetic effect to keep the HR down – theres also baroreceptors and chemoreceptors keeping the HR and BP down
in CHF, there’s less parasympathetic activity and increased B1 and adrenergic activity
the baroreceptors and chemoreceptors are more activated because they’re trying to get higher perfusion to organs in the body which increases BP
what are the harmful effects of adrenergic receptor activation in CHF?
- cardiac myocyte growth = B1
- fibroblast hyperplasia = B2
- myocyte damage/myopathy = B1
- fetal gene induction = B1
- myocyte apoptosis = B1
- proarrhythmia = B1, B2, A1
- vasoconstriction = A1
what happens to the homeostatic regulation of contractile function in CHF?
contractility decreases because adrenergic drive goes up but fails so cardiac function goes down
this is due to increased and constant bombardment of B receptors by NE (mostly)
so there’s increased NE which leads to increased B receptor signal transduction which subsequently leads to adverse biological effects on cardiac myocytes and progressive myocardial dysfunction/remodeling
this all ultimately causes a decrease in function and heart failure
what causes wall stress in CHF?
- increased cardiac pressure and volume overload
this leads to hypertrophy, bad fibrosis, contraction of smooth muscle and dysfunction of endothelial cells with loss of vasodilators
- neurohormonal effect causes oxidative stress which also leads to walls tress
these both lead to cardiac dysfunction and impaired perfusion
