HFPEF Flashcards
(22 cards)
What are the hallmarks of HFPEF? 3
LV hypertrophy, left atrial dilation and diastolic dysfunction.
Although, these are the hallmarks, they are not present in all patients and are not always present together.
Do all patients with HFPEF present with the hallmarks?
No, 1-2/3rds of patients do not present with LVH and those who do have hypertrophy can present with either eccentric or concentric.
What is Titin? And what is its function?
Titin is a large sarcomeric protein that functions as a molecular spring, stroking energy during contraction and releasing it during relaxation. The resting tension of the cardiomyocyte is highly dependent on Titin.
Name Titans 2 isofroms.
N2B (stiffer)
N2BA (longer)
What is ribonuleic acid binding motif-20?
It is a splicing factor of Titin. It’s inhibition results in more compliant Titin isoforms and thus a reduced resting tension.
Which pathways phosphorylation Titin? 6
1) cyclic adenosine monophosphate (cAMP)-defendant protein kinase A: Activated in response to beta-adrenergic stimulation by catecholamines.
2) cyclic guanosine monophosphate (cGMP) dependent protein kinase G (PKG): which is activated by nitric oxide or natriuetic peptides
3) Protein kinases Calpha, protein kinase II are activated by endothelium 1 and angiotensin II.
What does phosphorylation do to Titin? 2
PKA and PKG reduce cardiomyocyte resting tension whereas PKCalpha increases it.
Why do patients with patients with abnormal cardiomyocyte calcium present with increased diastolic resting tension?
Increased resting tension is due to persistent actin-myosin cross bridge activation due to elevated levels of calcium.
Why do patients with HFPEF have elevated levels of calcium?3
1) Abnormalities in the sodium-calcium exchanger
2) Calcium leakage from the sarcoplasmic reticulum
3) decreased SERCA activity
How can changes in the myocardial ECM result in HFPEF?
Increases in the collagen volume fraction is thought to contribute to diastolic dysfunction. It has a been found that degree of collagen cross-linking has been associated with filling pressures.
What is arterial stiffness associated with? 1
Exercise intolerance
What is an increased afterload associated with? 3
1) LV hypertrophy
2) HF
3) Fibrosis
The new paradigm for HFPEF proposes that myocardial remodeling and dysfunction results from a sequence of events consisting of the following: 6
1) Comorbidities, especially obesity induce a systemic pro-inflammatory state.
2) Because of this pro-inflammatory state, coronary micro vascular cells produce ROS, which limits NO bioavailability for adjacent cardiomyocytes.
3) Limited NO bioavailability decreases PKG activity in cardiomyocytes.
4) Low PKG activity removes the brake on cardiomyocyte hypertrophy, thereby induce concentric LV remodeling
5) Furthermore, the low PKG activity results in hypophosphorylation of the giant cytoskeletal protein Titin, which increases passive stiffness in the cardiomyocytes.
6) both stiff cardiomyocytes and increased collagen deposition by myofibroblasts, cause diastolic LV dysfunction.
What factors are produced by comorbidities that induce systemic inflammation? And why is this relevant to HFPEF? 2
The various comorbidities result in secretion of pro-inflammatory cytokines two of which are IL-6 and TNF alpha, both of which are elevated in HFPEF.
Explain the relationship between microvascular endothelial inflammation and NO bioavailability.5
1) HFPEF is characterized by systemic inflammation.
2) This systemic inflammation results in overexpression of vascular cell adhesion molecule (VCAM) and E-selectin.
3) the expression of these molecules leads to activation and subendothelial migration of circulating leukocytes.
4) Furthermore, the pro-inflammatory cytokines elicit endothelial production of ROS.
5) This results in low bioavailability of NO.
What is the relationship between NO and PKG activity? 2
NO stimulates the production of cyclic guanosine monophosphate (cGMP). CGMP activates PKG. Therefore, a decrease in NO, reduces production of cGMP reducing activation of PKG.
How does PKG contribute to cardiomyocyte hypertrophy, relaxation and stiffness?
Hypertrophy: PKG functions as a break on myocardial hypertrophy.
Myocardial relaxation: high levels of peroxynitirite increases phosphatatase 2a activity which lowers phosphorylation of phospholamban which decreases activity of SERCA. There is a decrease is Ca uptake and an increase in diatstolic cytosolic calcium resulting in an inability for the cardiomyocyte to relax.
Stiffness: Titin is phosphorylated by PKG and PKA and functions a physiological spring to maintain passive stiffness.
What does the diastolic myocardial dysfunction results from? 6
The pro-inflammatory state results in the release of TGFbeta which the differentiation of fibroblasts into myofibroblasts. This results in a pro-fibrotic state leading to an increased collagen volume fraction, higher expression of collagen type I and increased collagen cross-linking. These characteristic combined with the stiff cardiomyocytes result in diastolic dysfunction.
In HFPEF, arterial hypertension consists of increased SBP and a normal DBP. Explain why?
1) In HFPEF, LV dimensions are small and especially in the presence of LV hypertrophy, the left ventricle operates at a favorable Laplace relationship. LV systolic wall stress therefore remains low despite increased LV systolic pressure
What measures are required for a diagnosis of HFPEF?
1) Anthropometric measures,
2) comorbidities
3) vascular hyperemic response
4) plasma marker of oxidative stress and inflammation.
What should future HFPEF treatment strategies aim to do?
Cure arterial hypertension and endothelial dysfunction
How can endothelial dysfunction be treated?
1) NO donors
2) PDE-5 inhibitors
3) Anti-oxidative medication such as statins.
