Preclinical Studies on the Effects of Frailty in the Aging Heart.

Age is a major risk factor for the development of cardiovascular diseases in men and in women. However, not all people age at the same rate and those who are aging rapidly are considered frail, compared with their fit counterparts. Frailty is an important clinical challenge because those who are frail are more likely to develop and die from illnesses, including cardiovascular diseases, than fit people of the same age. This increase in susceptibility to cardiovascular diseases in older individuals might occur as the cellular and molecular mechanisms involved in the aging process facilitate structural and functional damage in the heart. Consistent with this, recent studies in murine frailty models have provided strong evidence that maladaptive cardiac remodelling in older mice is the most pronounced in mice with a high level of frailty. For example, there is evidence that ventricular hypertrophy and contractile dysfunction increase as frailty increases in aging mice. Additionally, fibrosis and slowing of conduction in the sinoatrial node and atria are proportional to the level of frailty. These modifications could predispose frail older adults to diseases like heart failure and atrial fibrillation. This preclinical work also raises the possibility that emerging interventions designed to "treat frailty" might also treat or prevent cardiovascular diseases. These findings might help to explain why frail older people are most likely to develop these disorders as they age.

Chronic angiotensin-converting enzyme inhibition attenuates frailty and protects against atrial fibrillation in aging mice.

BACKGROUND: Aging is a major risk factor for atrial fibrillation (AF); however, not all individuals age at the same rate. Frailty, which is a measure of susceptibility to adverse health outcomes, can be quantified with a frailty index (FI). OBJECTIVE: This study aimed to determine the effects of angiotensin-converting enzyme (ACE) inhibition on AF and atrial remodeling in aging and frail mice. METHODS: Aging mice were treated with the ACE inhibitor enalapril for 6 months beginning at 16.5 months of age and frailty was quantified. AF susceptibility and atrial structure and function were assessed by intracardiac electrophysiology in anesthetized mice, high-resolution optical mapping in intact atrial preparations, patch clamping in isolated atrial myocytes, and histology and molecular biology in atrial tissues. RESULTS: Enalapril attenuated frailty in aging mice with larger effects in females. AF susceptibility was increased in aging mice but attenuated by enalapril. AF susceptibility and duration also increased as a function of FI score. P-wave duration was increased and atrial conduction velocity was reduced in aging mice and improved after enalapril treatment. Furthermore, P-wave duration and atrial conduction velocity were strongly correlated with FI score. Atrial action potential upstroke velocity (Vmax) and Na+ current (INa) were reduced whereas atrial fibrosis was increased in aging mice. Action potential Vmax, INa, and fibrosis were improved by enalapril and also correlated with FI scores. CONCLUSION: ACE inhibition with enalapril attenuates frailty and reduces AF susceptibility in aging mice by preventing atrial electrical and structural remodeling.

Lifelong longitudinal assessment of the contribution of multi-fractal fluctuations to heart rate and heart rate variability in aging mice: role of the sinoatrial node and autonomic nervous system.

Aging is a major risk factor for sinoatrial node (SAN) dysfunction, which can impair heart rate (HR) control and heart rate variability (HRV). HR and HRV are determined by intrinsic SAN function and its regulation by the autonomic nervous system (ANS). The purpose of this study was to use multi-scale multi-fractal detrended fluctuation analysis (MSMFDFA; a complexity-based approach to analyze multi-fractal dynamics) to longitudinally assess changes in multi-fractal HRV properties and SAN function in ECG time series recorded repeatedly across the full adult lifespan in mice. ECGs were recorded in anesthetized mice in baseline conditions and after autonomic nervous system blockade every three months beginning at 6 months of age until the end of life. MSMFDFA was used to assess HRV and SAN function every three months between 6 and 27 months of age. Intrinsic HR (i.e. HR during ANS blockade) remained relatively stable until 15 months of age, and then progressively declined until study endpoint at 27 months of age. MSMFDFA revealed sudden and rapid changes in multi-fractal properties of the ECG RR interval time series in aging mice. In particular, multi-fractal spectrum width (MFSW, a measure of multi-fractality) was relatively stable between 6 months and 15 months of age and then progressively increased at 27 months of age. These changes in MFSW were evident in baseline conditions and during ANS blockade. Thus, intrinsic SAN function declines progressively during aging and is manifested by age-associated changes in multi-fractal HRV across the lifespan in mice, which can be accurately quantified by MSMFDFA.

Heart Failure With Preserved Ejection Fraction in the Elderly Population: Basic Mechanisms and Clinical Considerations.

Heart failure with preserved ejection fraction (HFpEF) refers to a clinical condition in which the signs of heart failure, such as pulmonary congestion, peripheral edema, and increased natriuretic peptide levels, are present despite normal ejection fractions and the absence of other causes (eg, pericardial disease). The ejection fraction cutoff for the definition of HFpEF has varied in the past, but recent society guidelines have settled on a consensus of 50%. HFpEF is particularly common in the elderly population. The aim of this narrative review is to summarize the available literature regarding HFpEF in elderly patients in terms of evidence for the age dependence, specific clinical features, and underlying mechanisms. In the clinical arena, we review the epidemiology, discuss distinct clinical phenotypes typically seen in elderly patients, the importance of frailty, the role of biomarkers, and the role of medical therapies (including sodium-glucose cotransport protein 2 inhibitors, renin-angiotensin-aldosterone system blockers, angiotensin receptor/neprilysin inhibitors, diuretics, and ß-adrenergic receptor blockers). We then go on to discuss the basic mechanisms implicated in HFpEF, including cellular senescence, fibrosis, inflammation, mitochondrial dysfunction, enhanced production of reactive oxygen species, abnormal cellular calcium handling, changes in microRNA signalling, insulin resistance, and sex hormone changes. Finally, we review knowledge gaps and promising areas of future investigation. Improved understanding of the specific clinical manifestations of HFpEF in elderly individuals and of the fundamental mechanisms that contribute to the age-related risk of HFpEF promises to lead to novel diagnostic and treatment approaches that will improve outcomes for this common cardiac disorder in a vulnerable population.