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Cardiovascular ageing represents a major burden for elderly patients and healthcare providers. The current impressive increase of life expectation highlights the need to understand the (patho)physiology of ageing in order to define potential therapeutic strategies to confront this challenge. Among many unresolved issues, the age-related progressive reduction of myocardial efficiency certainly represents one of the most fascinating.
Age-related reduction of cardiac cellular metabolic reserve
In normal myocardium, the concentrations of the high-energy phosphate compounds ATP and phosphocreatine (PCr) are tightly controlled over a range of performance because ATP production by mitochondrial oxidative phosphorylation is closely coupled to ATP utilisation by cytosolic adenosine triphosphatases. ATP is the direct energy source for energy-consuming reactions in the cell, while PCr acts as an energy storage compound and, in addition, as an energy transport molecule in the ‘creatine kinase-PCr energy shuttle’. Previous clinical studies using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) to measure PCr/ATP ratios in human myocardium have shown that this ratio is reduced in hypertrophied and, even more so, in failing human myocardium. In their Heart manuscript, Nathania1 investigated a possible relation between age and PCr/ATP ratio and cardiac power in healthy women by cardiac MRS with 31P spectroscopy and maximal graded cardiopulmonary exercise testing.1 PCr/ATP ratio, peak cardiac power, diastolic function and peak exercise oxygen consumption were significantly lower in old compared with young age group. PCr/ATP ratio showed a significant positive relationship with diastolic function, peak cardiac power output and peak oxygen consumption. These results indicate that high-energy phosphate metabolism and peak power of the heart decline with age. Additionally, based on the positive relationship between PCr/ATP ratio, early-to-late diastolic filling ratio and peak cardiac power output, they confirm that cardiac high-energy phosphate metabolism may be an important determinant of cardiac function and performance. The concept that myocardial high-energy phosphate metabolism decreases with age is an interesting contemporary notion that could become the basis for a novel approach to deal with ageing and age-related cardiac diseases.
Cardiac cellular metabolic reserve and heart failure
Myocardial high-energy phosphate metabolism regulates cardiac function and performance. Depletion of PCr and free creatine levels has been described as a uniform phenomenon occurring in heart failure of various origins. The decrease in creatine content/creatine kinase activity has been shown to correlate with the degree of left ventricular dysfunction. On this ground, attempts to increase cellular energy reserve in heart failure have already been pursued. In rats after myocardial infarction, the decrease of total creatine content was prevented by ACE inhibition.2 β-Blockade has been shown to induce symptomatic and functional improvement in patients with heart failure in association to increased PCr/ATP ratio, indicating drug-induced preservation of myocardial high-energy phosphate levels.3 Thus, the beneficial effects of these established therapies on mortality seen in clinical trials could be, at least in part, related to changes in improved cardiac metabolic efficiency. Other studies have also shown that metabolic drug modulators could improve PCr/ATP ratio in patients with heart failure.4 5
In the presence of severely reduced left ventricular systolic function and after accounting for multiple comorbidities that are common in older patients, age remains a strong, independent determinant of exercise capacity and ventilatory efficiency. In the HF-ACTION study, age was the strongest predictor of peak VO2. The observation by Nathania1 that high-energy phosphate metabolism and performance of the heart decline with age and yield a positive relationship with peak cardiac power output in healthy women suggests that reduced cardiac high-energy phosphate metabolism could play a significant role in the context of borderline cardiac conditions. In this study, resting and exercise systolic blood pressures were higher in the older age group. Since blood pressure is an important determinant of cardiac energy consumption, it could have well determined the observed reduction in PCr/ATP ratio in this group. A previous study has indeed shown that PCr/ATP ratio in healthy young adult men is inversely associated with heart rate,6 which is the other important determinant of cardiac energy consumption.
Reduced cardiac cellular metabolic reserve and ‘unsuccessful ageing’
Elderly is often associated to frailty, a biological syndrome that reflects a state of decreased physiological reserve to confront with stressors in advanced age. Although little is known about how frailty translates into ‘unsuccessful ageing’, frailty is often defined as impaired physical or cognitive functioning and increased vulnerability to physiological stressor. It may represent a driving factor for destabilisation of elderly patients, commonly leading to acute decompensated heart failure. Apart from systolic dysfunction, heart failure with preserved ejection fraction (HFpEF) is certainly the most frequent cause of cardiac decompensation in elderly frail subjects. There is a growing epidemic of HFpEF. This form of heart failure presents usually with a normal-sized left ventricle and often, but not always, with hypertrophy of cardiac chambers walls. Pre-existing diastolic dysfunction in the presence of precipitating factors (uncontrolled hypertension, arrhythmias, infections, and so on) may end up in acute systolic dysfunction and pulmonary oedema. Approximately 50% of patients hospitalised for heart failure have HFpEF, and the mortality risk for these patients is equivalent to those with heart failure accompanied by reduced ejection fraction. Cardiac and skeletal muscle metabolic impairment due to mitochondrial dysfunction has been indicated as a main pathophysiological mechanism.
Several attempts to find an effective therapy for such conditions have failed over the years. However, a not yet tested hypothesis is that deranged myocardial metabolism could play a substantial role in the onset, maintenance and progression of HFpEF in frail elderly individuals.
A combination of exogenous and endogenous stressors, that is, nutritional and environmental stress, unbalanced ratio between matrix metalloproteases and their inhibitors, altered mitochondrial biogenesis/autophagy and redox status, may be crucial on determining frail conditions. These factors promote oxidative stress, lipid accumulation, decreased glucose uptake and ketogenesis, thus leading to reduced cardiac metabolic function, that is, incapability to produce more energy or reduced energy production and potentially contributing to heart failure and potential decompensation.
Monitoring myocardial metabolic levels: therapeutic implications
Could the described age-related cardiac metabolic phenotype be the pathophysiological basis of heart failure with preserved ejection fraction? Could we do something to slow down this apparently irremediable age related process? Regular exercise could certainly be of great help. Better physical fitness could explain better muscle energetics, regardless of age. In the Nathania’s study, subjects were matched for physical fitness habits. However, in a previous similar study, the PCr/ATP ratio was significantly reduced in the older compared with the middle and young age groups but was significantly affected by physical activity level. High-active young and older women demonstrated higher PCr/ATP ratio than low-active women. Interestingly, high-active older women had PCr/ATP ratio similar to that of young but low-active women. Additionally, middle-aged women tended to have higher values of PCr/ATP ratios than younger women for matched activity level. However, in older women, physical activity had no effect on eccentricity ratio E/A ratio, torsion and peak cardiac power output. These findings suggest that high-level physical activity preserves cardiac metabolism and exercise capacity with ageing but has limited effect on age-related changes in concentric remodelling, diastolic function and cardiac performance.7 Another study has shown that trained middle-aged subjects exhibit a better pattern of left ventricular energy metabolism and of diastolic function than their sedentary counterparts. At this age, the exercise-related cardiac benefits were detectable when physical exercise was performed regularly and for a long period of time.8
All these concepts should prompt us to monitor cardiac metabolic levels and try to improve them by effectively dealing with pathological conditions that could be deleterious and adopt healthy lifestyles. Physical exercise and blood pressure and heart rate reduction are certainly among the best and affordable approaches to pursue this aim. We will not conquer immortality, but we could probably put the heart in a better shape to cope with other typical pathological conditions of the elderly patient, such as infections and brady–tachy arrhythmias which, whenever they will arise, could eventually confront with a fitter heart and finally determine less damage.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.