Traditional understanding of heart failure
Historically, heart failure was thought to be a disorder of its pumping function and the ejection fraction (EF); therefore, these became an important component and determinant of the condition. The increasing prevalence of heart failure with preserved ejection fraction (HFPEF) and the current lack of disease-modifying therapy for this group of patients raise the question again of whether we truly understand the mechanisms that drive the entire spectrum of the heart failure syndrome. How can all the different described types of heart failure be linked up to create a spectrum and a story that is easily understandable? Can we link the relationship of the core mechanism of heart failure with EF and then with the types of HF such as heart failure with reduced ejection fraction (HFREF), HFPEF or even with the old classification of high-output, low-output, forward and backward failure, right and left heart failure? Unless we progress further in answering these questions, discovering treatment for the entire heart failure population will be difficult.
Damage, fatigue and injury concept
For chronic heart failure, there may be three basic but linked mechanisms that exist to cause the heart failure: damage, fatigue and injury.
The damage mechanism is very evident in the common myocardial infarctions1 or some toxic/inflammatory cardiomyopathies (eg, anthracycline chemotherapy-induced cardiomyopathy or chronic myocarditis)2 and is naturally associated with reduced EF (HFREF). Here, there is a large amount of irreversible myocardial damage leading subsequently to fibrosis; the heart failure is systolic and is due to pump failure.
However, myocardial injury can often be transient, acute and limited, such as with acute viral myocarditis causing myocardial inflammation and oedema, or other reversible cardiomyopathies (injury of an undefined nature in peripartum cardiomyopathy, a sympathoexcitation-induced injury in Takotsubo cardiomyopathy or a hypermetabolic injury in heart failure related to a thyroid storm).3 It would not be unreasonable to assume that the reversible forms of left ventricular (LV) systolic dysfunction are the ones where injury has played a part but significant damage has not occurred (the injury group). There could be variable amounts of injury and damage caused by alcohol, chemotherapeutic agents or other drugs, catecholamines, infections and so on with the final outcome on LV function determined by the proportion of injury versus damage. Genetic causes or myocardial infiltration would most likely also fall under the injury versus damage headings.
Myocardial fatigue may be the cause of heart failure if the ventricle is having to pump against high vascular resistance.4 5 This may be the main mechanism of HF in patients with HFPEF as there is increasing evidence that microvascular dysfunction6 7 is probably the key operating mechanism in this variety of heart failure. Data have been presented to suggest that patients with HFPEF are likely to be progressing from a stage of preclinical diastolic dysfunction to the HFPEF stage with increasing left ventricular end-diastolic pressure (LVEDP) as assessed by echocardiographic E/E′. 8 It can be speculated that the elevated LVEDP is related to the LV struggling to pump into a high-pressure vascular circuit that is a result of microvascular dysfunction. Ageing9–11 has an important role in gradually increasing arterial resistance as have comorbidities12 such as hypertension13, diabetes14 15 and chronic kidney disease.16 17 There is probably additional contribution to this vascular ageing from changes in the heart itself of both microvascular rarefaction and myocardial fibrosis (including perivascular fibrosis), which reduces coronary flow reserve resulting in LV diastolic dysfunction.18
Cardiac fatigue has been described in athletes,19 20 is reversible and appears to affect ventricular diastolic function21 more than systolic function. The above hypothesis is, therefore, plausible. While fatigue in the early stages would manifest as increased LVEDP with preserved LV systolic function, prolonged or severe fatigue would naturally lead to systolic dysfunction and pump failure (which may be reversible if the fatigue can be tackled by say controlling poorly controlled blood pressure22) probably because of the development of focal and diffuse myocardial fibrosis that accompanies severe fatigue. Systemic hypertension, the the most common and most important cause of HFPEF, causes myocardial fatigue as a result of the enhanced vascular stiffness against which the LV has to pump. Another parallel example of fatigue would be HF related to conditions such as hypertrophic obstructive cardiomyopathy (HOCM)23 and severe aortic stenosis,24 which increase LVEDP by causing intramyocardial resistance to blood flow at the level of the left ventricular outflow tract and the stenotic aortic valve, respectively. In these conditions, the heart failure is usually of the HFPEF type as the ventricle is having to pump against high resistance (which is at the cardiac rather than at the vascular level), with a consequent increase in LVEDP. Interestingly, intervention to reduce the high resistance, such as an aortic valve replacement for severe aortic stenosis, can result in recovery of the LV fatigue,24 particularly in those without myocardial fibrosis,25 presumably as the myocardium in these patients is in a state of chronic fatigue that has not reached an advanced stage that is accompanied by fibrosis. On the other hand, advanced and prolonged fatigue can result in irreversible myocardial changes of hypertrophy and fibrosis26 as seen in some patients with severe untackled aortic stenosis with no cardiac reserve. In other words, recovery is linked to the stage of fatigue. Advanced fatigue with extensive fibrosis is unlikely to recover.
Advanced myocardial fibrosis that is seen in both patients with aortic stenosis (AS)27 and patients with HOCM28 may be a consequence of chronic progressive fatigue through myocyte loss, but in HOCM, myocardial abnormalities including hypertrophy and fibrosis also have a genetic basis. In non-obstructive hypertrophic cardiomyopathy, the hypertrophy and fibrosis are genetically determined and lead to a purely cardiac cause of HFPEF due to LV diastolic dysfunction with little contribution from vascular stiffness.
Looking at the phenotypes of AS from a fatigue angle, AS with preserved LVEF would correspond to early LV fatigue with preserved EF and stroke volume at the expense of elevated LVEDP. Later when LVEDP rises substantially, LV filling becomes impaired leading to low-flow, low-gradient AS with preserved LVEF, but the stroke volume and cardiac output would have reduced. Finally, as advanced fatigue sets in, there is fibrosis due to myocyte loss, LVEF starts to fall and the ventricle starts to dilate leading ultimately to a dilated ventricle with reduced EF, the so-called low-flow, low-gradient severe AS with depressed EF. A ventricle suffering from uncorrected advanced fatigue can, therefore, end up looking like one that is a result of damage. The pathophysiology of the end stage, however, is likely to be different in the fatigued ventricle with focal and diffuse fibrosis occurring in a chronic slow fashion as opposed to fairly rapid fibrosis that occurs due to damage during infarction or inflammation.
High-output cardiac failure29 would also be an example of fatigue-related heart failure as a result of the myocardium’s inability to cope with an enhanced volume of blood.