CVPR 03-31-14 08-09am Heart Failure & Hypertrophy - Buttrick Flashcards
Response of heart to acute hemodynamic & adrenergic stimuli
- Altered P/V relationships….. 2. Altered inotropy ….. 3. Altered chronotropy
Response of heart if hemodynamic/adrenergic stimuli persists
Adult heart is able to alter its size & shape in response to chronic stresses
Cariac dilation – characteristics
Myocyte length increases much more than myocyte width increases…. Extensive fibrosis….. myocyte death….. advanced cardiac dysfunction
Physiological hypertrophy – characteristics
Myocyte length increases more than myocyte width increases (long & skinny)….. No fibrosis…. No cardiac dysfunction
Myosin Heavy Chain Isoforms
Alpha & Beta MHC isoforms are found in the heart —> Three heterodimers are possible (αα, αβ and ββ), with distinct ATPase activity (and functional properties)….. The ratio of these isoforms varies across species & throughout development , as well as in response to disease… alpha & beta MHC are encoded by different genes & their expression is transcriptionally regulated
More ATPase —>
increase HR (as in heart of person who exercises)
Cardiac hypertrophy & shifts in Myosin isoform & ATPase
Shifts in myosin isoforma & ATPase are seen in phenotypically distinct models of cardiac hypertrophy…. In pathological hypertrophy, there is a decrease in ATPase and increase in Beta-Beta MHC (slow ATPase myosin)….. In physiological hypertrophy, there is an increase in ATPase & in alpha-alpha MHC (fast ATPase myosin)
Contemporary view of the heart
Cardiac adaption is a dynamic process involving not only architectural but also structural modifications….. In response to stress, both quantity & quality of contractile elements is altered ….. The heart has phenotypic & genotypic plasticity ….. Programmatic alterations in gene & protein expression occur in response to pathologic or physiologic triggers, with phenotype adaptions involving both transcriptional & post-translational modifications….. Functional adaptations are generally adaptive but over time can result in ventricular dysfunction
Time domains of physiologic responses to pressure overload
1st: Left ventricular hypertrophy w/mechanical manifestations (increased end diastolic pressure; increasing to accommodate the increased afterload of HTN) ….. Later: Heart failure (can’t generate the volume or pressure at a give preload/muscle length
Left Ventricular Hypertrophy : Cellular Mechanisms of change
Likely increase in Ca current via L-type Ca channel….. Reduced SR pump fxn (↑ PLB/SERCA2 ratio)….. Impaired myofilament relaxation….. Altered (increased) cytosolic Ca2+ 7 new steady-state
Hypertrophy: Alterations in signaling processes
Early/acute changes (adaptive): PKA-driven inotropy….. Chronic changes: PKC-epsilon, PKD, CAMk (calcineurin) etc. …. All these impair relaxation and act on contractile machinery, leading to hypertrophic remodeling
SERCA2 Gene Transfer as Therapy
SERVA2 gene transfer (infect w/virus encoding SERAC2) has been found to be sufficient to correct mechanical defects in cardiocytes from pts w/ HF (currently in clinical trials)
Altered transcriptional regulation of gene expression
Activation of TF which impact at different places along the gene, able to drive alpha rather than beta myosin head chains, for example; EX: Calcineurin (Ca2+-dependent phosphatase; slow responder/not active with acute & transient stimuli such as exercise, etc.) can dephosporylate MFAT, which moves to nucleus & influences transcription —> large & dysfunction hearts in mice
Left ventricular function following acute insult
Acute insult causes initial sharp decline in ejection fraction….. but, even a while after the acute insult, heart function (ejection fraction) continues to decline & further deteriorate (positive feed-back mechanisms that amplify disease severity, such as through neurohormonal system, ventricular remodeling, RAAS, myogenic response…. If can block any of these, can perhaps stop the cycle)
