diastolic heart failure-do we need a two (or more) hit theory?

Warning The following represents the musings of a non-cardiologist,clearly unqualified by training to speak with much credibility on this subject.

The earliest recognizable phase (s) of diastolic dysfunction seems to happen to everyone if they live long enough and late middle age may be long enough. This phase is labelled, in the jargon of echocardiography, as "impaired relaxation" and  according to the latest expert guidelines technically as " E/A ratio less than or equal to 0.8 and E  wave velocity less than or equal to 50 cm/sec."These values are obtained by measuring blood flow with Doppler technique across the mitral valve. Relaxation occurs simultaneously with elastic recoil (aka restoring forces) from which there is no current method to distinquish it.Authors addressing this topic seem fond of the spring analogy and it has been suggested that the world's largest protein molecule,titin,functions like a spring.

 To perhaps overly simplify a complex process,let us consider diastole or ventricular filling as a three phase event, pre-early, early and late.See end note 1 Pre-early is the phase after the aortic valve closes and before the mitral valve opens (the isovolumic relaxation phase),early is the phase when blood flow rapidly into the ventricle ( as  depicted by Doppler technique as the E wave) ,late is when blood is pushed from the atrium by contraction and represented a the A wave. In the young E is greater than A and remains so probably until about late middle age.when the E wave is no longer higher than A, the echocardiographer  now usually says "impaired relaxation"

The party line current theory describes the early phase of diastole as being driven by relaxation and diastolic suction. Extensive data show that several indices of  diastolic function change in the process of healthy aging. The ventricle takes longer to relax which is signaled   by a prolonged isovolumic relaxation time or IVRT. There is also slowing of the early flow across the mitral valve  depicted by a lower E wave velocity and a lower E/A ratio.

The early mitral velocity of blood flow decreases and the IVRT lengthens- changes believed to represent impaired relaxation and is reported as such on echo reports. (Even though it is generally agreed that there is no way to partition the relative effects of relaxation and diastolic suction as they occur at the same time.)  Simplistically diastolic suction function can be thought of elastic recoil,the release of the stored energy created by contraction. This is also referred to as restoring forces.  The late phase of diastole is influenced by the stiffness or compliance of the ventricle and the contractility of the atrium.

One of the missions of echocardiography is non-invasively estimate the "filling pressure" of the left side of the heart. Filling pressure is the  pressure at the end of diastole also referred to as preload.
Elevated filling pressure can be used to confirm or support the diagnosis of heart failure (HF) and is believed to correlate strongly with shortness of breath on exercise.

Since every one is thought to develop  a decrease early diastolic function but everyone does not develop diastolic heart failure ,could those patients with decreased ( or more decreased) ventricular compliance-which exerts its effect in late diastole- be the HFpEF candidates?

The story of the changes detected in the aging heart as depicted by the Group from Southwestern (1) goes like this:

Early on there is impaired relaxation.Left ventricular stiffening occurs during the transition period between youth and middle-age and "become manifest between the  ages of 50 to 64", This is followed by left ventricular volume shrinkage and remodeling ( wall thickening) after age of 65. So the sequence is impaired relaxation, stiffening and then remodeling.

There are data indicating that about 1/4 patients with stage 2 or 3 diastolic function    progress  to HF.(Impaired relaxation is stage 1, as ventricular stiffness builds up so does the pressure in the atrium and this is reflected with an increase in E ,and E/A increases , a pattern often referred to as pseudonormal (although the most recent ASC guidelines no longer use that term) , as things get worse the LA pressure increases more and values change appropriately earning the designation of restrictive pattern (again this is the older terminology banished by the 2016 revised guidelines)

So maybe a second hit is needed. One such hit could well be prolonged hypertension and the resultant concentric hypertrophy of the heart leading  to decreased ventricular compliance, or at least "ventricular chamber compliance".Left ventricular myocardial changes seen in obesity and diabetes could also represent a second hit and could contribute to both diastolic dysfunction and systolic dysfunction.

Myocyte apoptosis occurs with aging is accompanied by hypertrophy of the surviving myocytes and increase in fibrosis, all of which could conspire to stiffen the ventricle  as well as impairing relaxation.

The group from  Dallas (2) has presented data that a sedentary lifestyle can cause concentric cardiac hypertrophy and that prolonged aerobic exercise  ( at levels as least twice that of the standard exercise prescription which would be about 5 hours of moderate exercise per week) if started by early middle age may prevent the age related loss of ventricular compliance It should be noted that there are data and interpretation of data that contradict that hypothesis. See here  and here for commentary regarding the observations that more aerobic exercise is required to prevent diastolic heart failure that is sufficient to decrease the risk of coronary artery disease.

Diastolic heart failure is a well recognized companion of diabetes .Several possible second hit suspect mechanisms  have been described  in diabetes including deposition of glycation products and increase in myocardial cell tension.

Of course there is much more to it than that. Normal healthy aging per se has been associated with apoptotic loss of heart muscle cell,compensatory hypertrophy of remaining muscles cells and fibrosis leading to some stiffening of the ventricles with the only apparent "hit" being aging. But again that seems to happen to everyone and everyone does not develop diastolic heart failure.Maybe a second hit is needed and again according to the Dallas group a sedentary lifestyle may be one such second hit second hit.See here for commentary on effect of sedentary lifestyle on cardiac remodeling .

In broad, non specific terms the "second hit" is anything that increases cardiac stiffness.





1) Fujimoto,N. Effect of ageing on left ventricular compliance and distensibility in healthy sedentary humansThe Journal of Physiology2012 590 (pt 8)1871 (see end note 2)

2) Dr Benjamin D Levine N Fujimoto Paul Bhella and others have published extensively examining the effect of ageing,exercise and the lack of exercise on various aspects of cardiac function and age related impairment. They posit that long term endurance exercise begun at lest by middle age may prevent the loss of compliance that is common in sedentary human evens in the absence of the usual suspect heart problems (HBP,diabetes,obesity)


end note 1.I know there are "really 4 stages" I left out "diastasis"
end note 2. If anyone can explain to me the difference between compliance and distensiblity please comment.

Addendum 3/16/18 A few more additions to try and get this thing right.

Might meta analyses and meta data dreging gaslight everyone

Two dueling meta-analyses come to mind. There was a widely quoted meta analysis regarding Vitamin E which concluded it increased the risk of death. Soon after that article appeared in the Annals of Internal Medicine, letters to the editor claims that using a different statistical technique on the same data base, there was no increase in death risk.

Large data bases and multiple comparisons between outcomes and variables seem to always show that some factor becomes a risk factor for something often with relative risk values less than 2 and often less than 1.5.RR.Values in this range are unlikely per se to  unearth a causative factor.This activity is sometimes referred to as "data dredging"  or looking for a positive correlation to rush to print and press releases.

The prudent researcher usually emphasizes that these finding are "hypothesis generating" and not game changing breakthroughs although  the less prudent and the lay press and astro-turf propaganda outlets may suggest the latter. When apparently contradictory data then appear in the medical (and then the popular) press what is one to believe. This seems to be a cousin of "gas lighting" even though no one is plotting to make anyone doubt their ability to reason and analyze medical  data but  tons of data and sounding alarms on the findings of many  of them may have a similar effect of "not knowing what to believe".