From the Bottom of our Hearts

Q: What's the difference between physiological and pathological hypertrophy of the heart and how does pathological hypertrophy lead to heart failure while physiological hypertrophy does not?

A: This question certainly isn't dumb, as scientists are still trying to work out the answer to this date!

Physiological hypertrophy is often seen in athletes and pregnant women and is characterised by being reversible, comprising healthy myocardium and devoid of associated symptoms of Heart Failure. [2]

Pathological Hypertrophy is often seen in conditions like Aortic Stenosis and Hypertension, where the hypertrophy is accompanied by irreversible scarring,fibrosis and symptoms of heart failure. [2] 

Types of Cardiac Hypertrophy: ( Source: Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefactionFirst published June 1, 2006)


We'd like to answer this by looking at how hypotheses were made and challenged over the years

Initial theory: Persistence?:

Initially it was believed that the chronicity of insult caused pathological hypertrophy of the heart, as the the insult was prolonged giving the heart lesser time to develop an adequate physiological response. 

This was suggested as a result of studies where they compared heart function between mice who were exercise trained and mice who had a banding of the aorta performed on them (which reduced the diameter of aorta and increased afterload pressures). [2]

II Is there something more?:

Perrino et al [1]  conducted an interesting experiment where with the latest techniques he was able to introduce transverse constrictions in the aorta of mice, this time he could control the application of constriction and in his first study he divided the mice into three groups:

a)  Mice with cTAC (Chronic transverse constriction of aorta)
b) iTAC (Intermittent transverse constriction of aorta)
c) Mice subjected to exercise

His findings showed that the mice with exercise showed a physiological response, and the mice with cTAC showed a pathological response, but what was interesting is, the mice with iTAC showed features of both physiological and pathological hypertrophy, which established that there was something more than just the chronicity that played a role here.

 It was found out that the pressure overload from the intermittent constriction of aorta led to a prolonged sympathetic drive that caused downregulation of regular B adrenergic receptors and upregulation of receptors like P13kY and BARK1 on the myocardium, causing maladaptive hypertrophy. [1]

 In mice subjected to β blockade and inactivated forms of p13kY, some of the pathological hypertrophy features were not observed, and multiple studies showed the presence of several other receptors, and chemical mediators that govern cardiac hypertrophy.

III Chemical and Mechanical mediators?

One of the chemical pathways that determines pathological hypertrophy involving Protein kinase C, Calcineurin and P13K (source: Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies: Bianca C.BernardoaKate L.WeeksabLynettePretoriusacJulie R.McMullena)
Other studies have shown the importance of various factors like:

a) Secretion of gene altering proteins called calsarcins by Z discs of the myocardium in the setting of pressure overload. [2]

 b) Hormonal Mediators like as insulin-like growth factor-1 (IGF-1) and transforming growth factor beta (TGF-β) acting on tyrosine kinase-coupled receptors (RTKs) in physiological hypertrophy and G-protein-coupled receptors (GPCR)-activating molecules, such as catecholamines, angiotensin II, and endothelin-1, in pathological hypertrophy [2]

c) Role of inflammatory mediators like cytokines such as interleukins (IL)-6, IL-1β, IL-1RA, TNF-α, nuclear factor kappa B (NF-κB) in Post MI conditions [2]

Studies are still underway to find out how different insults selectively affect different receptors and the molecular basis of these signalling pathways.

Clinical Application:

The recognition of the harmful effects of prolonged sympathetic drives and activity of the Renin-Angiotensin-Aldosterone system gave rise to the practice of using RAS blockers like spironolactone, ARBS, ACE inhibitors and β blockers to prevent cardiac remodelling in patients of Heart failure. [2]

References:

[1] Perrino C, Naga Prasad SV, Mao L, et al. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J Clin Invest. 2006;116(6):1547–1560. doi:10.1172/JCI25397


[2] Samak M, Fatullayev J, Sabashnikov A, et al. Cardiac Hypertrophy: An Introduction to Molecular and Cellular Basis. Med Sci Monit Basic Res. 2016;22:75–79. Published 2016 Jul 23. doi:10.12659/MSMBR.900437

By Ashwin Mahesh

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