Introduction
Heart Failure (HF) is defined as a complex clinical syndrome with symptoms and signs that result from any structural or functional impairment of ventricular filling or ejection of blood (ACC)1.
It is now widely recognized as a massive health and economic burden across the whole world which is increasing exponentially due to the aging population.
Myocardial energy deficiency and subsequent altered metabolic pathways are increasingly being recognized as an essential part of the heart failure jigsaw2,3. Ongoing research has identified numerous changes which occur in the myocardium at the molecular level and in cardiac metabolism. However, the exact etiopathology behind these molecular changes of heart failure elude us.
In addition, up to half of the cases 4,5,6,7 with heart failure suffer from Heart Failure with Preserved Ejection Fraction (HFPEF). It has been shown that progressive worsening of diastolic dysfunction is associated with increased incidence of heart failure 8. However, the pathophysiology behind this progressive worsening has not been clearly understood.
We seek to reconcile these seemingly disparate processes of diastolic dysfunction and energy deficiency into a single unified pathophysiological cycle incorporating the effects of myocardial circulatory insufficiency acting as a binding force via which the two feed off each other causing progressive heart failure. This is essentially due to the unique nature of myocardial blood circulation which relies heavily on the diastolic phase of the cardiac cycle, as well as patterns of oxygen utilization and an insatiable energy appetite which is the hallmark of myocardial cells.
Diastolic Dysfunction
Cardiac diastole is a phase where the myocardium returns to an unstressed length and force after systolic contraction. Diastolic dysfunction may be defined as any abnormality in the form of prolongation, slowing or incompleteness in the diastolic phase of the cardiac cycle.
Components of Diastolic Function
Cardiac diastole is a function of two arbitrarily9 separate but interrelated processes namely active relaxation and passive stiffness.
Active Relaxation
Myocardial relaxation occurs in a series of energy-consuming steps10–14 (Figure 1). Adequate energy supplies and the mechanisms to regenerate them must be present for ventricular relaxation to occur at a sufficient rate and extent 11,13,14. In the left ventricle, myocardial relaxation results in pressure decline at a constant volume (Isovolumic relaxation) followed by a filling phase at variable pressures (Auxotonic relaxation) and then continued filling mediated by atrial systole.

(ATP – Adenosine Triphosphate, PKA – Protein Kinase A)
Passive Stiffness
Several intracellular and extracellular structures contribute passive viscoelastic properties to the myocardium, which determine its stiffness. The intracellular endo sarcomeric protein like titin is useful in using part of the energy from systolic contraction of the heart and storing it as potential energy which is dissipated and provides a recoiling force, when the myocardium returns to its resting length during diastole. It also prevents the myocardium from overstretching during the filling phase of the diastole and possibly uses part of the filling pressures during atrial systole to support the systolic contraction via the same mechanism of stored potential energy. Titin isoforms can change in conformation and have been shown to have increased stiffness in end stage heart failure. Similarly microtubule density and distribution changes have been seen to impart increased viscoelastic passive stiffness to the failing heart. Changes in extracellular fibrillar collagen synthesis and degradation and their regulatory proteins can also have consequences leading to development of diastolic heart failure.
We believe that these changes can occur due to 2 possibilities: genetically inherited cardiomyopathies have abnormalities in structural proteins since birth and lead to altered mechanical responsiveness of the myocardial tissue during cardiac cycle. Alternatively, they can occur as a compensatory adaptive mechanism in response to pressure or volume overload. However, due to disorganized growth, it contributes to further deterioration and progression of the pathology of heart failure. These acquired changes are reversible if the primary insult is temporary or if it is adequately treated and is probably the reason why some cardiomyopathies show excellent remodeling potential while some continue to progress despite best efforts. Nevertheless, it is quite clear that non-contractile structural elements within and around the myocardium also can attenuate or exacerbate the effects of hemodynamic changes during the cardiac cycle and play their part towards progression or supporting improvement of heart failure.
Actin Myosin Cycling in Muscle Contraction and Relaxation
As per the currently accepted theory of muscle contraction15 the shortening of the myofibrils occurs due to a stepwise interaction between the actin and myosin filaments. These steps are described as follows (Figure 2): a) Action potential causing the release of calcium from sarcoplasmic reticulum b) Calcium ion binding to troponin causing troponin-tropomyosin complex to move exposing the binding site on actin molecule for the myosin head and myosin head-actin cross bridge formation c) movement of the myosin head (using energy derived from ATP hydrolysis) causing a power stroke d) fresh ATP binding to myosin head to cause detachment from actin followed by repetition of the cycle. It is important to identify that apart from being the energy supply for the power stroke, ATP supply is also important for the detachment of the myosin head from the actin filament and other active processes in diastole.

(ATP – Adenosine Triphosphate, ADP – Adenosine Di-phosphate, iP – inorganic phosphate)
Establishing the positional role of ATP
ΔG~ATP is the free energy generated from ATP hydrolysis and is utilized by cardiac myocytes for processes like force generation and ion homeostasis16. Pharmacologic17 or ischemic18 inhibition of ATP synthesis can produce a decline in ΔG~ATP prior to the onset of contractile dysfunction. This is primarily mediated by an increase in [ADP]19 via feedback-inhibition of ATPase reactions at SERCA pump, Myosin and Na+/K+ channel. Cardiac myocytes autoregulate [ATP] close to ~10mmol/L20 such that [ATP] and [Pi] remain unchanged despite increasing workloads21. Thus, the ADP driven decline in ΔG~ATP can be considered as the primary manifestation of impaired cardiac energetics and the energy deficit worsens with increased work demands22–24. It has also been shown in animal models of MHD (HFHS Rats) where ΔG~ATP decreases to a level that is too low to maintain normal diastolic and systolic function16.
Regulation of Active Relaxation by [ADP]
Calcium dissociation from TnC (Troponin C) and detachment of actin-myosin crossbridge have been proposed as possible rate limiting steps in myocardial relaxation25. Increase in [ADP] can adversely affect cross bridge cycling and SERCA2a pump activity by reducing the activity of their ATPase reactions. During cross bridge cycling if some myosin heads remain attached to the actin molecule as an intact crossbridge, the myocyte remains in a partially contracted state with increased resting tone during diastole26. Similarly, decreased activity of the SERCA2a pump leads to residual cytosolic Ca2+ which does not return to the baseline and slows cross bridge cycling by keeping the binding sites exposed due to its continual attachment to the Troponin complex26. This phenomenon has been observed in many studies and given several different names in the past like “diastolic contracture”27, “diastolic stiffness”28, “resting tension”26, “decreased LV chamber volume” “decreased LV cavity size”29, but they essentially indicate diastolic dysfunction. It also shares similarities with the state of rigor mortis in skeletal muscles post mortem causing contractures after depletion of [ATP]30. Thus, as per available evidence, rising [ADP] due to progressive energy deficit culminates into diastolic dysfunction31–33.
Coronary Blood Flow
The human heart has its own unique blood supply mechanism. Although its chambers remain filled with blood, this pool does not contribute to maintaining the viability or function of the heart34. Instead, cardiac function and viability are maintained by a specialized coronary circulation with an outside-in blood supply35 where the blood is supplied by epicardial coronary arteries that further divide and penetrate into the myocardium. The major site of coronary vascular resistance exists in microvascular beds that ultimately supply an extremely dense myocardial capillary network (~3000–4000 capillaries/mm2)36.
The heart also has the highest per gram oxygen consumption of any organ, extracting up to ~70% to 80% of delivered oxygen even under resting conditions37–39. This means that any further enhancements to oxygen extraction are rather limited40 and maintenance of coronary perfusion is vital to supply oxygen as well as other nutrients and sustain the production of high energy phosphates. Thus, the heart has developed a unique and specific metabolism-perfusion balance to meet the demands of its continuous high workload.
Extravascular Compression and Transmural Flow Distribution
As per Ohm’s Law (Flow = ΔPressure/Resistance), blood flow is directly proportional to the magnitude of the pressure gradient (arterial – venous) across the vascular tree and inversely proportional to the overall resistance of the vascular network.
The pressure itself is the difference between transmural expansive pressures forcing outward against the vascular wall and compressive tissue pressures counteracting that expansion. In the majority of organs, the compressive tissue force is constant and therefore is considered to make only a minimal yet consistent contribution to the pressure gradient so that the forward flow is mainly during systole. However, the periodicity of ventricular contractions and tremendous compressive forces of the myocardium counteract the systolic blood flow. As a result, around 80% of antegrade blood flow to the left ventricle occurs during diastole37,38. This also creates an inversion between the flow patterns in the left and right ventricles41–44.
Additionally, compared to other non-compressible tissues, where the arterial to venous pressure difference determines tissue perfusion, myocardial blood flow is determined by the gradient between diastolic blood pressure and intramyocardial tissue pressure45–48. Hence, it may be inferred that inability of the myocardium to adequately relax is detrimental to its own perfusion.
Coronary Flow Reserve (CFR)
Coronary flow reserve (CFR) is defined as the ratio between coronary blood flow at maximal hyperemia and the resting coronary blood flow49. Several modalities can be used to measure CFR invasively as well as non-invasively. Non-invasive modalities include echocardiography50, positron emission tomography (PET)51, and cardiac magnetic resonance (CMR)52. However, invasive53 modalities with doppler flow velocity and thermodilution can also be used. Recently a systematic review and meta-analysis on CFR54 has shown that reduced coronary flow is strongly associated with increased risk of all-cause mortality and MACE across a wide range of pathological processes.
Thus, CFR can be considered as a reflection of subclinical microvascular disease burden. Hence, a decreased CFR indicates depletion of residual coronary vasodilatory capacity and any further derangements will translate into inadequate myocardial perfusion.
Uniqueness of Cardiac Metabolism
Fatty acid (FA) oxidation serves as a major source of energy (60-90%) for the myocytes while carbohydrates and multiple other substrates can also be potentially used depending on the metabolic conditions. The myocardium also has very limited anaerobic capacity 55,56. The net energy yield of long-chain FA oxidation is much higher (105 ATP per molecule of Palmitic acid) compared to glucose (31 ATP) and anaerobic metabolism (2 ATP). The fetal heart utilizes glucose and lactate as its main energy sources, however after birth this gradually transitions towards FA oxidation which becomes the predominant energy source thereafter57. Thus, this metabolic switch provides a major energy boost but effective FA oxidation is only guaranteed under an abundant supply of oxygen58,59.
Cardiac Metabolism in Heart Failure
Heart failure has been shown to diminish the mitochondrial capacity to oxidize FA and ATP production becomes inefficient60.
Similarly, it has been shown in conditions such as those leading to cardiac hypertrophy and in heart failure that there occurs a reverse switch to a fetal type energy metabolism61. This is accompanied by re-expression of several isoforms of enzymes, of transcription factors, and of structural and other proteins normally expressed in the fetal heart62. This switch is considered to enable cardiomyocytes to maintain ATP production with lesser oxygen and is also seen in chronic hypoxia due to several pathological conditions63.
A decrease in palmitate utilization64,65 has been demonstrated in rats with cardiac hypertrophy from pressure overload and in myocardial infarction as has a reduction in oleate oxidation in pacing induced heart failure in dogs66. Similar findings have been noted in human studies involving patients with nondiabetic dilated cardiomyopathy and patients with idiopathic cardiomyopathy67,68. Rodent heart failure models also show downregulation of CPT 1 and 2, which are important components of the carnitine shuttle64,69.
Reduced levels of the enzymes responsible for beta oxidation of very-long chain and long-chain FA, VLCAD, and LCAD has also been noted and is thought to be responsible for a “backlog” in fatty acid metabolism, resulting in accumulation of toxic lipid intermediates in the heart, further aggravating the metabolic derangements in heart failure69–71.
In summary, the cumulative data from multiple animal and human studies demonstrates increased dependence on inefficient metabolic pathways like glycolysis, causing progressive energy deficit 64,72 in the failing heart.
Functional Capacity
Functional capacity is the ability of an individual to perform aerobic work as defined by maximal oxygen uptake (VO2max), that is, the product of cardiac output and arteriovenous oxygen (a – VO2) difference at physical exhaustion73. It is generally believed that VO2max is limited by maximal cardiac output rather than peripheral factors74. Endurance training can augment VO2max by 10-30% mainly by increasing the cardiac output73 as any enhancements to oxygen extraction are rather limited and myocardium also has very limited anaerobic capacity55,56.
Cardiac Tolerance Cycle
We seek to propose a model explaining progressive heart failure as a cyclic interplay between diastolic dysfunction and energy deficiency due to impaired myocardial perfusion (Figure 3).

This cycle may essentially start at any point:
a) Ischemia due to atherosclerotic coronary insufficiency, impaired microvascular flow (diabetic or hypertensive microangiopathy).
b) Impaired diastolic function or lusitropy due to tachycardia, hypertension, LVH, myocardial infiltration, etc.
c) Direct ATP deficiency due to metabolic disorders or nutritional deficiency like Beriberi, starvation, etc.
Irrespective of the starting point, unless the underlying cause is corrected, it forms a vicious loop wherein diastolic dysfunction impairs myocardial blood flow which is essential for delivering adequate oxygen required for ATP production. This in turn causes progressive energy deficit and culminates into worsening diastolic dysfunction. Depending on the severity of the initial insult the cycle may progress rapidly causing acute decompensated heart failure or operate in a quiescent state causing chronic heart failure.
The cardiac tolerance cycle sets a physiologic limit for the heart and acts as a failsafe mechanism causing manifestations of effort tolerance. Diastolic dysfunction has been shown to limit exercise tolerance and functional capacity even in individuals who do not have diastolic dysfunction at rest75. We believe that voluntary exertional activities are naturally discontinued at individual functional capacity under the influence of this cycle with resultant recovery of all the factors of the cycle ie. diastolic dysfunction, myocardial circulation and energy deficiency. However, a persistent event like a tachyarrhythmia or acute stress sustains this cycle beyond physiologic limits and leads to acute heart failure.
The cardiac tolerance cycle can also get partially activated by chronic persistent stressors eg. Diabetic microangiopathy or increased afterload due to Hypertension, etc. In these conditions, compensatory mechanisms keep this process insidious by attenuating the effects of each factor of the cycle. Altered metabolic pathways attempt to maintain ATP production through upregulation of glucose and downregulation of FA oxidation76. Initially, they can help to maintain cardiac function, but eventually they get completely exhausted and the cycle gets fully activated. At this stage, the progressive nature of the cycle overwhelms the adaptive responses causing abnormal cardiac remodeling, microcirculatory insufficiency and inefficient ATP production. This leads to gradual cardiac myocyte apoptosis with fibrotic infiltration and culminating in heart failure.
Individual links between Cardiac Tolerance Cycle
Current understanding of the pathophysiology of heart failure considers components of this cycle in isolation or in binary form. The associations between individual components of the cardiac tolerance cycle have been established over the last few decades (Figure 4). However, establishing a cyclic relationship helps to assimilate the complex interplay between these components and understand its role in the progression of heart failure from an asymptomatic to advanced state.

Red Arrow77–80 Green Arrow82,83,84,85 Purple Arrow31,86,87 Blue Arrow81
Diastolic dysfunction has been implicated as a determinant of myocardial circulation even in the absence of coronary artery disease in studies based on CFR77–80. Conversely, several studies have shown that myocardial circulatory insufficiency produces diastolic dysfunction in acute conditions like AMI (Acute Myocardial Infarction) as well as in chronic CAD (Coronary Artery Disease)82–85. Similarly, diastolic dysfunction associated with energy deficit has been documented in multiple animal studies14,86. Recent studies involving animal models fed with HFHS (High Fat High Sucrose) diet also seem to provide useful insights into this relationship22.
Toersten Doenst et. al. studied the effect of pressure overload on Sprague-Dawley rats and concluded that decreased rates of substrate oxidation with activation of compensatory metabolic pathways predicts development of HFPeF and subsequently HFReF81.
Current staging of Heart Failure1 by ACC/AHA identifies Stage A as individuals at risk due to underlying comorbidities and Stage B as Pre HF with established features of diastolic dysfunction or deranged cardiac markers. As such there remains a gap in our understanding as to why these individuals in stage A are at an increased risk or the mechanisms of progression to Stage B and C heart failure. We believe that cardiac tolerance cycle helps to explain the various phenotypes of heart failure in a more unified manner and provides the missing link to understand the mechanism of their progression. The cyclic interplay between diastolic dysfunction, energy deficit and myocardial circulatory insufficiency causes sequential exhaustion of compensatory mechanisms and ultimately leads to progression of heart failure.
We propose that instead of considering these 3 components separately we should consider them and their compensatory mechanisms as a composite phenomena. The relative exhaustion of these compensatory mechanisms is at play right from the asymptomatic at-risk stage where an earlier identification and intervention may be able to prevent progression or even reverse changes of heart failure.
Pathophysiological Conditions
Hypertrophic and Infiltrative Cardiomyopathies
An increase in cardiac mass with accompanying diastolic dysfunction and resultant imbalance between the vascular supply and myocyte requirements is the hallmark of pathological hypertrophy. This mismatch creates a chronic ischemic environment with energy deficit causing progressive activation of the cardiac tolerance cycle. This compromises essential survival processes for myocytes and promotes apoptosis with fibrotic infiltration. This may lead to development of eventual systolic heart failure and even dilated cardiomyopathy.
The ischemia and structural changes also affect the conduction system and predispose to development of arrhythmias. We believe that in the absence of epicardial coronary stenosis, the typical ECG changes of widespread ST depression observed in HCM are a reflection of the global microvascular ischemia.
Ischemic Cardiomyopathy
The cardiac tolerance cycle can be activated under conditions of ischaemia if the severity of the impact is sufficient enough to exhaust compensatory mechanisms. This may happen either suddenly (acute coronary syndrome or MINOCA) or gradually (chronic stable angina or microvascular dysfunction). However, subsequent steps like energy deficit, activation of diastolic dysfunction, adverse remodeling due to apoptosis followed by fibrotic infiltration and progressive heart failure are similar to what has been elucidated above.
Tachycardiomyopathy
We believe that the mechanism of persistent diastolic dysfunction and impaired intramyocardial blood flow due to severe persistent tachycardia plays a pivotal role in the development of tachycardiomyopathy. The increased heart rate severely reduces the diastolic relaxation time causing impaired diastolic coronary blood flow which causes severe energy deficiency as the myocardium is dependent on diastolic intramyocardial perfusion for oxygen and nutrient replenishment. This leads to further severe diastolic impairment and development of cardiomyopathy as the heart essentially strangulates itself. Resolution of tachycardia has been clearly shown to reverse this dysfunction which can be explained by the reversal of diastolic dysfunction and restoration of adequate energy supply to the heart.
Hypertensive Heart Disease and Diabetic Cardiomyopathy
Hypertension and Diabetes are the two most common comorbidities that lead to insidious progressive Heart Failure with Preserved ejection fraction. The mechanism and exact features of either pathology remain ill defined. We believe that our model of diastolic dysfunction, impaired microvascular flow (mirroring Diabetic and Hypertensive microangiopathy) and metabolic impairment causing a persistent energy deficiency and Diastolic Dysfunction is the underlying common pathological pathway causing progressive heart failure.
Failure of Drugs in improving Long Term Mortality
Decades of obsession with improvement of systolic function as a solution to fix the failing heart, has led to development and use of various inotropic drugs yet none have been found to significantly improve survival.
Recently management of heart failure has undergone a revolution with the implementation of a new 4 drug regimen. This consists of ARNI, Beta-blockers, SGLT2 inhibitors and Mineralocorticoid receptor antagonist (MRA). This may also be supplemented by Ivabradine to further reduce the heart rate. SGLT2 inhibitors were initially designed as diabetes drugs but serendipitously proved to be useful in reducing morbidity, mortality and hospitalizations due to heart failure. These drugs not only improve cardiac remodeling but also reduce afterload and have multiple other beneficial effects.
We believe that these drugs act synergistically to correct the energy deficit, diastolic dysfunction and myocardial circulation and hence help to attenuate the effects of heart failure despite having no direct inotropic action.
Conclusion
The uniqueness of the myocardial metabolism and its blood flow mechanisms along with a continuous unrelenting workload makes for an insatiable energy appetite which can mainly be satisfied during the diastolic phase of the cardiac cycle.
Latest research has rejuvenated the concept of energy deficiency in heart failure and more avenues are being explored to correct this energy deficiency through substrate modification like NAD+, short chain fatty acids (scfa’s) etc.
Newer drugs like Mavacamten have received approval for the management of HOCM with its unique mechanism of allosteric myosin inhibition to curb the excess actin-myosin crossbridge formation thus improving LVOT obstruction and perhaps diastolic dysfunction.
The human body is governed by a complex circadian rhythm which controls all homeostatic mechanisms, vital parameters and hormonal cycles. This is at odds with modern lifestyle which is predominantly sedentary, stressful and not in sync with our sleep-wake cycle. The intermittent surges of stress hormones in response to stimuli and longer awake times especially at night lead to persistently recurrent episodes of tachycardia, abnormal spikes of blood pressure and impair the cardiac diastole. In addition the lack of regular exercise and unhealthy diet downregulates our capacity to deal with stressors, due to a decrease in CFR. Constant stimulation by an overactive sympathetic “fight or flight” response, depletes the energy reserves at the cellular level and sets up the perfect stage for the development of a cardiac tolerance cycle.
We believe rather than trying to look for a single wonder drug as a solution to heart failure we should direct our efforts towards monitoring and improvement of functional capacity in asymptomatic at-risk individuals. Functional capacity has been shown in several clinical trials as an accurate predictor of cardiovascular mortality and morbidity. We encourage the use of CFR, PCr (Phospho-Creatine) and myocardial strain as a measure of the relative saturation of the compensatory mechanisms of the factors affecting the cycle and subclinical disease burden. The benefits from regular exercise, certain categories of pharmacological drugs and other non-pharmacological measures like meditation, yoga etc. have been known for several years. However, it is the associations of this cycle and its components as well as the molecular basis of functional capacity that enables us to accurately measure the effect of interventions at an individual level and set realistic targets with reliable indicators, to titrate these interventions specific to that particular individual. This holds the promising advantage of not only halting the effects of the cardiac tolerance cycle at an early stage but also its effective reversal in the future.
Abbreviations
ACC American College of Cardiology
ADP Adenosine Di Phosphate
AHA American Heart Association.
AMI Acute Myocardial Infarction
ARNI Angiotensin Receptor Neprilysin Inhibitor
ATP Adenosine Tri Phosphate
Ca Calcium
CAD Coronary Artery Disease
CFR Coronary Flow Reserve
CMR Cardiac Magnetic Resonance
CPT Carnitine Palmitoyl Transferase
ECG Electrocardiogram
FA Fatty Acid
HCM Hypertrophic Cardiomyopathy
HF Heart Failure
HFHS High Fat High Sucrose
HFPEF Heart Failure with Preserved Ejection Fraction
HFREF Heart Failure with Reduced Ejection Fraction
HOCM Hypertrophic Obstructive Cardiomyopathy
LCAD Long Chain Acyl-CoA Dehydrogenase
LVH Left Ventricular Hypertrophy
LVOT Left Ventricular Outflow Tract
MACE Major Adverse Cardiovascular Events
MHD Metabolic Heart Disease
MINOCA Myocardial Infarction with Non Obstructive Coronary Arteries
MRA Mineralocorticoid receptor antagonist
NAD Nicotinamide Adenine Dinucleotide
PCr Phospho-Creatine
PET Positron Emission Tomography
PKA Protein Kinase A
SCFA Short Chain Fatty Acid
SERCA Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase
SGLT Sodium Glucose co-Transporter
TnC Troponin C
VLCAD Very Long Chain Acyl-CoA Dehydrogenase
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