HFPEF Flashcards
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.
