Unsuccessful ageing: from frailty to cardiovascular disease

This editorial refers to ‘Changes in frailty and incident cardiovascular disease in three prospective cohorts’, by D. He et al., https://doi.org/10.1093/eurheartj/ehad885.

An adage of clinical wisdom posits that a person’s true age is determined by the health of their arteries and muscles, not by the number of years they have lived.

In this issue of the European Heart Journal, He et al. report their comprehensive post hoc analysis of three prospective ageing cohorts (CHARLS from China, ELSA from the UK, and HRS from the USA).¹ The population studied consisted of community-dwelling older adults without known cardiovascular disease (CVD) at baseline, amounting to a pooled sample size of 19 685 with an average age of 62 years. The predictor variable was frailty as measured by a 28-item frailty index (FI), which was categorized as robust (FI ≤0.10), pre-frail (FI 0.11–0.24), or frail (FI ≥0.25). Longitudinal transitions between frailty states were examined from the first to the second assessment at 2–3 years. The outcome variable was incident CVD (‘angina, heart attack, congestive heart failure, other heart problem, or stroke’) as measured by self-report at 5–10 years after the second assessment. Cox regression was used to determine the association between frailty transitions and incident CVD over time. The regression model was adjusted for age, sex, body mass index, marital status, education, smoking, alcohol use, physical activity, blood pressure, glycated haemoglobin (HbA_1c), HDL-cholesterol, and C-reactive protein (CRP). Residual confounders not accounted for included cardiac function and behavioural factors such as diet, stress, and sleep patterns.

The first finding of note relates to the prevalence of frailty transitions, with 75% remaining in the same category, 20% making minor transitions (from frail to pre-frail, pre-frail to robust or frail, or robust to pre-frail), and <5% making major transitions (from frail to robust, or robust to frail). Improvements in frailty were, for the most part, mediated by resolution of the mobility-related impairments, with extremely rare resolution of the disease- or disability-related impairments (since a hypothetical individual with diabetes, visual impairment, and difficulty preparing meals is usually guaranteed to retain these impairments). Only 10 of the 28 impairments could be considered as plausible candidates for normalization and hence de-frailing in this scheme. This, coupled with the relatively short time frame between assessments, explains why most patients remained the same frailty-wise. The second finding of note relates to the impact of frailty transitions, with worsening frailty conferring a two-fold greater risk of incident CVD. Numerous sensitivity analyses were reported, reaffirming these findings with different FI cut-offs and a third FI assessment, and also excluding CVD events occurring in the first year to ensure that the CVD was not indolently prevalent at the time of the FI assessment.

Does worsening frailty bring about the development of CVD, and, if so, how? Mechanistically, studies have shown that frailty and CVD share common connections with nefarious markers of inflammation, oxidative stress, insulin resistance, and procoagulation.² Notably, chronic low-grade inflammation drives the age-related loss of skeletal muscle known as sarcopenia, a core component of physical frailty, just as it drives the development of atherosclerosis and promotes plaque instability leading to acute coronary syndromes. Amyloid deposition causes Alzheimer’s dementia in the brain, just as it has been shown to infiltrate the heart and cause diastolic dysfunction leading to heart failure.³ Systemic hypertension is a joint risk factor for the development of vascular cognitive impairment, coronary artery disease, and heart failure. Sedentariness is yet another joint risk factor for the development of frailty and CVD, with a direct tie between the inactivity criterion for frailty and coronary artery disease. Genome-wide association studies have identified shared single nucleotide polymorphisms linking physical frailty, CVD, and metabolic syndrome.⁴ Epidemiologically, the study of He et al. and previous studies^5,6 have shown that this link is cross-sectional as well as longitudinal, and it is bidirectional, with frail patients being more likely to develop CVD, and CVD patients being more likely to develop frailty.

One may suspect that the deck was stacked to some extent given that cardiovascular risk factors (hypertension and diabetes) and classical cardiac symptoms (difficulty walking long distances, climbing stairs without resting, or carrying heavy weights) were included in He et al.’s iteration of the FI. Is this truly indicative of frailty causing CVD, or is it simply CVD risk factors re-branded as ‘frailty impairments’? These impairments accounted for 20% of the FI, so their potential impact is not trivial. Nevertheless, they fairly meet the three standardized criteria established by Searle and Rockwood for an impairment to be included in an FI:⁷ (i) it must be associated with ageing; (ii) it must be associated with adverse health outcomes; and (iii) it must not be ubiquitous in older adults. Unlike hypertension and diabetes, other cardiovascular risk factors such as dyslipidaemia and smoking fail to meet all three criteria (not meeting the first) and hence would not be eligible items for an FI. These guidelines for FI construction are helpful in research, but they can be counter-intuitive in practice. As a case in point, try justifying to a practising clinician that their patient’s heart failure with reduced ejection fraction (HFrEF), lymphoma, asthma, Crohn’s disease, and depression do not meet the age-associated criteria and hence do not count towards frailty.

Rockwood’s framework⁸ amalgamates a broad, diffuse, assortment of functional capacities, disabilities, diseases, and, in certain iterations, behaviours, symptoms, signs, and biomarkers. The FI performs best when it contains at least 20, ideally 40 or more, impairments. Akin to the ‘chicken soup’ of frailty scales, the FI tastes great (high predictive value for adverse events) but one cannot be sure what they are eating (low actionable value for targeted interventions). Fried’s framework,⁹ conversely, is the ‘steak dinner’ of frailty scales, with a narrow perspective on sarcopenia that unapologetically sacrifices the multisystem flavours in favour of a single system that is more directly measurable, interpretable, and actionable. Fried’s scale contains five impairments: slow gait speed, weak handgrip strength, low physical activity, low energy, and weight loss. Related scales often contain slow chair rises, balance tests, or imaging tests for muscle mass. While the FI can be computed retrospectively or even automatically from electronic health records (an advantage leveraged by He et al.), Fried’s scale requires human-administered questionnaires and physical performance tests. The latter returns quantitative outputs that are responsive to change for serial comparisons.

We, and others, have adopted a hybrid approach that tests physical performance and assesses multisystem domains inherent to frailty. The Essential Frailty Toolset (‘EFT’)¹⁰ was developed as a brief screening tool to predict 1-year mortality in older adults undergoing transcatheter aortic valve replacement or cardiac surgery, and it captures four domains: strength, cognition, anaemia, and hypoalbuminaemia. Intrinsic capacity¹¹ was developed by the World Health Organization as a construct to predict disability in older adults living in the community, and it captures five domains: (i) locomotion (strength, mobility, balance); (ii) vitality (energy, nutrition); (iii) cognition (memory, executive function, intelligence); (iv) psyche (mood, sociality); and (v) senses (hearing, vision). Intrinsic capacity is gaining momentum because it aligns with the re-framing of healthy ageing from disease-centric to function-based.¹² Older adults with high intrinsic capacity are set to remain independent and age in place, whereas those with low intrinsic capacity are prone to develop disability for activities of daily living and eventually require institutionalization. These trajectories are driven by a variety of upstream contextual factors, behaviours, exposures, diseases, subclinical impairments, and non-modifiable factors such as genetic predispositions and the ageing process itself, as shown in the framework for unsuccessful ageing (Graphical Abstract). The elaborated framework positions intrinsic capacity and allostatic capacity as the centrepieces of frailty, with the former reflecting the internal steady-state functioning and the latter reflecting the external stress response. Based on this framework, one can re-construct the gamut of frailty scales ranging from narrow assessments of locomotive intrinsic capacity (e.g. gait speed) to broad assessments of intrinsic capacities (e.g. mobility, nutrition, cognition, mood) plus its upstream drivers (e.g. diseases) and downstream consequences (e.g. disabilities).

Graphical Abstract.

Unsuccessful ageing. Contextual factors influence modifiable and non-modifiable determinants of health. Formative behaviours include diet, exercise, sleep, socialization, and avoidance of excess stress, smoking, alcohol, and drugs. Access to healthcare is instrumental to inform behavioural change and prevent the onset or progression of disease. Accumulation of diseases, as well as subclinical impairments in multiorgan functionality, erode the body’s allostatic and intrinsic capacities. Allostatic capacity relates to the restoration of physiological homeostasis in response to stressors and it is mediated by immune, endocrine, autonomic, hepato-renal, and cardiovascular systems. Intrinsic capacity relates to the preservation of autonomous functioning and it is mediated by locomotive, energetic, cognitive, psychological, and sensory faculties. If these faculties fall below a critical threshold, and they cannot be enabled by assistive technologies (e.g. a walking aid), then one becomes dependent for activities of daily living. Institutionalization, defined as living in an assisted care facility or hospital, is modelled as the end result of unsuccessful ageing in the absence of available caregivers to help perform activities within the home setting. Frailty has been operationally defined as narrowly as locomotive intrinsic incapacity (e.g. gait speed) or as broadly as summated intrinsic incapacities, allostatic load, upstream diseases, and downstream disabilities (e.g. frailty index).

In conclusion, the insightful study by He et al. has strengthened our appreciation of the bidirectional association between frailty and CVD. It has highlighted the multidimensional nature of frailty and its varied operating definitions depending on the school of thought and availability of data. Astute readers should develop the habit of probing the supplemental appendices to critically appraise the items included in any given frailty scale, asking whether the items are (i) associated with ageing and adverse health outcomes; (ii) precisely measured or passively observed; (iii) ‘chicken soup’ or ‘steak dinner’; and (iv) actionable or purely predictive. Frailty scales are not all created equal. Clinicians should view this study as yet another reason to integrate frailty into their routine evaluation of older patients, since frailty not only informs the procedural risk of mortality or morbidity but also informs the 5- to 10-year risk of incident CVD. What remains to be proven is whether CVD can be thwarted by de-frailing interventions such as strength training and dietary protein supplementation,^13,14 and whether older adults with evidence of frailty can benefit from intensified primary prevention and screening for CVD.

Declarations

Disclosure of Interest

The author declares no conflict of interest for this contribution.

Funding

J.A. is supported by the Canadian Institutes of Health Research (CIHR) and the Fond de recherche en santé du Québec (FRS-Q).