Introduction
The term ‘cardiometabolic disease’ (CMD) appears to have been initially used by the exercise physiologist, Pescatello and VanHeest [1], and refers to a combination or clustering of metabolic abnormalities that increases the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus [2]. These metabolic abnormalities include increased insulin resistance, hyperglycaemia, visceral obesity, nonalcoholic fatty liver, dyslipidaemia and hypertension [1,2]. The term may be used as a platform for examining how new pharmacological interventions can be employed to enhance clinical outcomes and improve survival in those with CMD.
The prevalence of CVD increases with age. In the US, the prevalence of CVD is around 54% for those aged 40–59 years, 78% for those aged 60–79 years and 90% for those aged >80 years [3]. The high prevalence of CVD in these age groups is linked to age-related factors such as increased oxidative stress, inflammation, apoptosis and overall myocardial deterioration and degeneration [4]. Frailty and sarcopenia are emerging new factors that promote a state of cardiometabolic abnormalities that increases the risk of CVD. Other age-related unhealthy behaviours such as inactivity, malnutrition and poor sleeping pattern are also factors linked to CVD [3]. This review will evaluate the risk factors that predict cardiometabolic disease in older people and explore ways of prevention. The review will also indicate that the separate specialities of cardiology and diabetes may not be able individually to address all the emerging and often overlapping complex metabolic disturbances requiring treatment, and that a new subspeciality is needed.
Prediction
The impact of traditional risk factors that predict CVD may change with increasing age. Also, there is emergence of new age-related cardiovascular risk factors such as frailty and sarcopenia.
Risk factors change and reverse metabolism
Longitudinal data have shown that with advancing age the predictive values of BMI and systolic blood pressure decline in relation to myocardial infarction and ischaemic stroke or heart failure, respectively. However, other risk factors such as LDL-cholesterol for myocardial infarction and BMI and fasting blood glucose regarding heart failure remained significantly predictable for incident CVD in old age [5]. A small observational study of 331 older adults, mean age 85 (7.0), has shown that low BMI, low diastolic blood pressure, low total and HDL cholesterol and high insulin sensitivity predicted total mortality indicating a reverse metabolism that is probably attributable to malnutrition with or without other chronic conditions. These inverse associations limit the relevance of conventional cardiovascular risk factors and suggest that future studies are needed to determine whether prevention and treatment of malnutrition would prevent cardiovascular events [6]
Role of frailty and sarcopenia
Frailty (a state of increased vulnerability to poor resolution of homeostasis after a stressor event) and sarcopaenia are now recognized as high impact complications association with diabetes [7]. Frailty and CVD appear to have a bidirectional relationship [8]. Frailty predicts CVD while CVD is associated with an increased risk of incident frailty and the coexistence of both frailty and CVD is associated with poor outcomes independent of age and comorbidities [9]. However, it is still not clear whether frailty is an independent risk factor for CVD and whether interventions to prevent frailty would prevent the development or slowdown the progression of CVD. Prefrailty has also been shown to independently increase the risk of CVD and those who were prefrail had an increased prevalence of cardiometabolic abnormalities such as insulin resistance, central obesity and increased inflammatory markers suggesting that frailty may promote an adverse cardiometabolic state that mediates the development of CVD [10]. Some obese individuals may have a lower muscle mass (sarcopenia) or lower muscle to fat ratio, a condition known as sarcopenic obesity. The combination of both obesity and sarcopenia may have a synergistic effect on the risk of CMD. A reduced muscle mass is associated with the accumulation of visceral fat including nonalcoholic fatty liver. Accumulated visceral fat induces chronic inflammation which contributes to the development and progression of loss of muscle mass. Therefore, a vicious cycle develops between the loss of muscle and the accumulation of visceral fat which leads to increased risk of atherosclerosis via a complex interplay of factors including increased insulin resistance, proinflammatory cytokines, increased dietary energy, reduced physical activity, increased oxidative stress and mitochondrial dysfunction [11]. (Fig. 1) Obesity is associated with increased accumulation of proinflammatory adipokines secreted by adipocytes. Serum adipokines are positively associated with visceral fat and negatively associated with muscle mass. The presence of sarcopenic obesity is independently associated with increased serum levels of adipokines suggesting that low grade inflammation mediated by adipokines is the main mechanism of the vicious circle between sarcopenic obesity and CMD [12]. On the other hand, skeletal muscles secrete beneficial myokines that increase glucose uptake and fatty acid b-oxidation in muscle, stimulate hepatic gluconeogenesis and induce lipolysis in adipose tissue. Thus, taken together, the vicious circle between muscle loss and fat gain might lead to more severe sarcopenia or obesity via changes in body composition and increases in the risk factors for CMD, which in turn increase the risk of CVD-related events [13]. Reduced muscle strength or dynapenia may also play a role in CMD risk. Subjects with sarcopenic obesity defined as reduced muscle strength in the Cardiovascular Health Study had an increased risk of CVD than those with sarcopenic obesity that was defined as low muscle mass. This may suggest that dynapenia is an important factor for CMD risk than the absolute or relative low muscle mass alone [14]. Also, dynapenic abdominal obesity has been recently shown to be independently associated with high prevalence of cardiometabolic risk factors [15].
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Fig. 1: The imbalance between muscle–fat ratio created by frailty and sarcopenia plays a crucial role in the pathogenesis of increased cardiometabolic risk.
Predictive tools
Current risk calculators have not been validated in older people making them inadequate for use in this population [3]. Because of the emergence of new cardiovascular risk factors in this age group, novel predictive tools are required. Relative hand grip strength (hand grip strength divided by BMI) has been shown to be significantly associated with favourable cardiometabolic risk factors such as blood pressure, lipid profile, triglyceride, fasting glucose, HbA1c, log high-sensitivity C-reactive protein (hs-CRP) and metabolic syndrome [16]. Hand grip strength, normalized to body mass, has also been shown to be robustly associated with cardiometabolic risk parameters in the US and the Chinese ageing adults [17]. These results suggest that hand grip strength can be used as a screening noninvasive diagnostic tool in identifying those at risk for future cardiometabolic impairment. Low gait speed also appears to be a useful predictor of future CVD [10]. Activin A is a growth factor that has multiple functions including regulating wound repair, apoptosis and cell differentiation. It has been shown that there is a dose-dependent association between serum activin A levels and frailty, cognitive impairment, malnutrition, metabolic syndrome, uric acid and hs-CRP. Therefore, activin A status may represent a novel biomarker of overall cardiometabolic risk in older people [18]. In view of the increased visceral obesity and reduced height caused by osteoporotic vertebral fractures and thinning of the intervertebral cartilage in older people, waist circumference may have a better predictive value than BMI in this age group [19].
Prevention
The prevention of CMD and its progression to CVD should involve maintenance of a healthy metabolic profile and control of the traditional cardiovascular risk factors.
Maintenance of a healthy metabolic profile
The disturbance of fat–muscle ratio caused by the development of sarcopenia and frailty leads to a reduced muscle mass and power (with associated decline in the protective myokines) and increased visceral fat (with associated increase in the harmful adipokines) causes a state of metabolic abnormalities that increases the risk of CMD and its progression to CVD. Therefore, the maintenance of healthy metabolic profile primarily includes the maintenance of muscle mass and power and the prevention of visceral fat accumulation. This is likely to be achieved through the combination of improved diet and regular exercise training.
Diet
It has been shown that older people with low Mediterranean diet (Med-Diet) adherence had higher BMI (P = 0.029), higher prevalence of arterial hypertension (P < 0.001), previous coronary (P = 0.002) and cerebrovascular events (P = 0.011), diabetes (P < 0.001) and dyslipidaemia (P = 0.001) compared with those with high adherence suggesting that improved Med-Diet adherence might potentially delay the onset of CMD [20]. Meta-analysis of observational studies have shown overall protective effects of Med-Diet on the risk of CVD [21]. Supplementing Med-Diet with more olive oil or nuts showed 30% reduction in major cardiovascular events in older people (55–80 years old) [22]. A prospective study of 2622 older people, mean (SD) age 74.4 (4.8), showed that higher levels of omega 3 polyunsaturated fatty acids from sea food source was associated with a lower risk of unhealthy ageing and suggests that dietary consumption of fish should be increased [23]. Vitamin D deficiency was found to be associated with higher cardiometabolic risk factors in older people although the clinical impact of this association is still not very clear [24]. High protein intake (35 g) after resistance training 3 days per week for a total of 12 weeks was associated with significant improvement in parameters of cardiometabolic profile compared with low protein intake (35 g placebo) in preconditioned older women [25].
Exercise
In the cardiovascular health study which included 4207 subjects, mean (SD) age 72.5 (5.5) years, greater physical activity was inversely associated with ischaemic heart disease, stroke and total CVD even in those ≥75 years. Walking pace, distance, and overall walking score, leisure-time activity and exercise intensity were each associated with lower risk. The findings for walking distance and pace are especially important given that walking is the most common type of physical activity in older people [26]. In a Finnish study of 2456 subjects aged 65–74 years, leisure-time physical activity reduced the risk of total and CVD mortality regardless of their baseline risk factors and the beneficial effect was dose dependent [27]. It has been shown that engagement in light intensity physical activity was independently associated with favourable HDL and total cholesterol profiles in older people with multiple chronic conditions [28]. High intensity interval training (HIIT) appears to have superior effects on cardiometabolic profile than moderate intensity continuous training [29]. Nonweight bearing all extremity HIIT appeared to be feasible and well tolerated in older people which may be an option for those with musculoskeletal and balance problems [30]. Even light physical activity may have a favourable cardiovascular benefit. Among 5861 older women, mean (SD) age 78.5 (6.7) years, the highest quartile of light physical activity, compared with the lowest quartile, was associated with a 42% reduction in the risk of myocardial infarction or coronary death [31]. Similarly, it was observed that modest levels of physical, but not necessarily vigorous, activity confer benefits in terms of CVD risk, compared with being completely inactive in older people above the age of 65 years [32]. Whole body electromyostimulation application has shown a favourable effect on the metabolic profile in community-dwelling women aged ≥70 years with sarcopenic obesity which may be considered an effective and well tolerated novel technology to prevent cardiometabolic risk in those who are unable or unwilling to exercise conventionally [33].
Control of traditional cardiovascular risk factors
Smoking cessation is beneficial even for those who quit later in life and should be part of multidimensional approach to risk factor modification in older adults with diabetes [34].
Hypertension
Hypertension is not only a risk factor for CVD but also increases the risk of cognitive impairment, renal failure and mortality. Reducing blood pressure to a target of 150/80 mmHg in the Hypertension in the Very Elderly Trial was beneficial in older people ≥80 years old regardless of the frailty status [35]. The Systolic Blood Pressure Intervention Trial (SPRINT) has shown that further reduction of systolic blood pressure to ≤120 mmHg is more beneficial than systolic of ≤140 mmHg, but this aggressive reduction has resulted in an increased number of side effects such as orthostatic hypotension, electrolyte abnormalities and acute kidney injury. Furthermore, this study had excluded patients with a history of diabetes, heart failure, dementia, stroke, weight loss of >10% and nursing home residence making it difficult to generalize its findings to the general population of older people [36]. There is also a concern for a J-shaped relationship with increased cardiovascular events for both low and elevated blood pressure [37]. Therefore, a target blood pressure of 140/90 mmHg should be considered in most older patients and a lower target of <140 mmHg systolic for those with a high cardiovascular risk and able to tolerate antihypertensive medications without side effects. A more relaxed target of 150 mmHg systolic is reasonable in patients who are frail, residents in care homes or have limited life expectancy.
Statins
In a French study of 7284 subjects, median age 80 years followed up for a median of 4.7 years, the use of statins was associated with a lower risk of outcomes in the primary prevention group that has modifiable risk factors [HR 0.93 per year of use; 95% confidence interval (CI), 0.89–0.96, P < 0.01] and in the secondary prevention group (0.75, 0.63–0.90, P < 0.01) but not in the primary prevention group that does not have modifiable risk factors (1.01, 0.86–1.18, P = 0.92) [38]. Similar results were confirmed in a recent meta-analysis of 28 randomized studies that showed that statin therapy was associated with 21% [relative risk (RR) 0.79, 95% CI, 0.77–0.81] risk reduction in major vascular events per 1.0 mmol/L reduction in LDL cholesterol. The beneficial effect of statins was similar, irrespective of age, among patients with pre-existing vascular disease (P = 0.2), but appeared smaller among older (>75 years) than among younger (≤55 years) individuals not known to have vascular disease (P = 0.05). This suggests that, in older people (>75 years), there is good evidence to support statin therapy in the secondary but not in the primary prevention of vascular events [39].
Glucose regulation
Hyperglycaemia is a risk factor for CVD and also increases the risk of geriatric syndromes such as cognitive impairment, frailty and falls in older people [40]. However, tight glycaemic control (HbA1c < 6%) does not provide cardiovascular protection and appears to be harmful in this group of patients [40]. Therefore, glycaemic control should be individualized with a target of 7.5% in healthy older patients, 8% for those with comorbidities and 8.5% for those who are frail or with limited life expectancy.
Aspirin therapy
Data on the benefits of aspirin in primary prevention in older people ≥70 years old are mixed, but recently, it has been shown that the use of aspirin as a primary prevention derives no benefits and is harmful to healthy community-dwelling older people [41].
Conclusion
With increasing age, there is a decline in the impact of the traditional cardiovascular risk factors on the risk of CVD. Instead, frailty and sarcopenia emerge as new factors that promote a state of cardiometabolic abnormalities such as increased insulin resistance and chronic inflammation that increases the risk of CVD. Assessment of frailty has been advocated as part of standard care for all healthcare sectors including cardiology specialist services [42] and as older adults with frailty have nearly a five-fold increase in major cardiac events [43], it is now time to integrate this assessment into cardiometabolic disease management. Further details of these assessment processes are available in our cited references [7,42], and emphasize the characteristics of the frailty and sarcopaenia phenotypes and how they can be measured in a straightforward and practical office-based manner.
Maintenance of a healthy metabolic profile through maintaining of muscle mass and reducing visceral fat by adequate diet and regular exercise combined with control of traditional cardiovascular risk factors may help reduce the progression into CVD.
Future perspectives
Although it appears that frailty and sarcopenia play a crucial role in the mechanism of the CMD and in turn its progression to CVD in older people, the pathogenesis still needs further understanding. It is also not clear whether interventions to prevent sarcopenia and frailty would reduce the incidence of CVD. Future predictive tools that measure the muscle–fat ratio as well as the introduction of novel therapeutic interventions are still required.
What is becoming evident is that the overlap between cardiology and diabetes is increasing and that it is unclear which speciality can manage all these various metabolic issues effectively without the need for more integration of therapeutic approaches. A call for developing a subspeciality of cardiometabolic medicine is sensible and overdue [44].
Conflicts of interest
There are no conflicts of interest.
References
1. Pescatello LS, VanHeest JL. Physical activity mediates a healthier body weight in the presence of obesity. Br J Sports Med. 2000; 34:86–93
2. El Hadi H, Di Vincenzo A, Vettor R, Rossato M. Cardio-metabolic disorders in non-alcoholic fatty liver disease. Int J Mol Sci. 2019; 20:2215
3. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al.; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation. 2019; 139:e56–e528
4. Curtis AB, Karki R, Hattoum A, Sharma UC. Arrhythmias in patients ≥80 years of age: pathophysiology, management, and outcomes. J Am Coll Cardiol. 2018; 71:2041–2057
5. Lind L, Sundström J, Ärnlöv J, Lampa E. Impact of aging on the strength of
cardiovascular risk factors: a longitudinal study over 40 years. J Am Heart Assoc. 2018; 7:e007061
6. Vischer UM, Safar ME, Safar H, Iaria P, Le Dudal K, Henry O, et al. Cardiometabolic determinants of mortality in a geriatric population: is there a ‘reverse metabolic syndrome’?
Diabetes Metab. 2009; 35:108–114
7. Sinclair AJ, Abdelhafiz AH, RodrĂguez-Mañas L. Frailty and sarcopenia – newly emerging and high impact complications of
diabetes. J
Diabetes Complications. 2017; 31:1465–1473
8. Afilalo J, Karunananthan S, Eisenberg MJ, Alexander KP, Bergman H. Role of frailty in patients with
cardiovascular disease. Am J Cardiol. 2009; 103:1616–1621
9. Afilalo J, Alexander KP, Mack MJ, Maurer MS, Green P, Allen LA, et al. Frailty assessment in the
cardiovascular care of older adults. J Am Coll Cardiol. 2014; 63:747–762
10. Sergi G, Veronese N, Fontana L, De Rui M, Bolzetta F, Zambon S, et al. Pre-frailty and
risk of
cardiovascular disease in elderly men and women: the pro.V.A. Study. J Am Coll Cardiol. 2015; 65:976–983
11. Sakuma K, Yamaguchi A. Sarcopenic obesity and endocrinal adaptation with age. Int J Endocrinol. 2013; 2013:204164
12. Kim TN, Won JC, Kim YJ, Lee EJ, Kim MK, Park MS, et al. Serum adipocyte fatty acid-binding protein levels are independently associated with sarcopenic obesity.
Diabetes Res Clin Pract. 2013; 101:210–217
13. Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012; 8:457–465
14. Stephen WC, Janssen I. Sarcopenic-obesity and
cardiovascular disease
risk in the elderly. J Nutr Health Aging. 2009; 13:460–466
15. Alexandre TDS, Aubertin-Leheudre M, Carvalho LP, MĂ¡ximo RO, Corona LP, Brito TRP, et al. Dynapenic obesity as an associated factor to lipid and glucose metabolism disorders and metabolic syndrome in older adults – findings from SABE study. Clin Nutr. 2018; 37:1360–1366
16. Lee WJ, Peng LN, Chiou ST, Chen LK. Relative handgrip strength is a simple indicator of cardiometabolic
risk among middle- aged and
older people: a Nationwide Population-Based Study in Taiwan. PLoS One. 2016; 11:e0160876
17. Peterson MD, Duchowny K, Meng Q, Wang Y, Chen X, Zhao Y. Low normalized grip strength is a biomarker for
cardiometabolic disease and physical disabilities among U.S. and chinese adults. J Gerontol A Biol Sci Med Sci. 2017; 72:1525–1531
18. Peng LN, Chou MY, Liang CK, Lee WJ, Kojima T, Lin MH, et al. Association between serum activin A and metabolic syndrome in older adults: potential of activin A as a biomarker of
cardiometabolic disease. Exp Gerontol. 2018; 111:197–202
19. Fan H, Li X, Zheng L, Chen X, Lan Q, Wu H, et al. Abdominal obesity is strongly associated with
cardiovascular disease and its
risk factors in elderly and very elderly community-dwelling chinese. Sci Rep. 2016; 6:21521
20. Vicinanza R, Troisi G, Cangemi R, De Martino MU, Pastori D, Bernardini S, et al. Aging and adherence to the mediterranean diet: relationship with cardiometabolic disorders and polypharmacy. J Nutr Health Aging. 2018; 22:73–81
21. Rosato V, Temple NJ, La Vecchia C, Castellan G, Tavani A, Guercio V. Mediterranean diet and
cardiovascular disease: a systematic review and meta-analysis of observational studies. Eur J Nutr. 2019; 58:173–191
22. Estruch R, Ros E, Salas-SalvadĂ³ J, Covas MI, Corella D, ArĂ³s F, et al.; PREDIMED Study Investigators. Primary prevention of
cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med. 2018; 378:e34
23. Lai HT, de Oliveira Otto MC, Lemaitre RN, McKnight B, Song X, King IB, et al. Serial circulating omega 3 polyunsaturated fatty acids and healthy ageing among older adults in the
cardiovascular health study: prospective cohort study. BMJ. 2018; 363:k4067
24. Chen CH, Liu LK, Chen MJ, Lee WJ, Lin MH, Peng LN, Chen LK. Associations between vitamin D deficiency, musculoskeletal health, and cardiometabolic
risk among community-living people in Taiwan: age and sex-specific relationship. Medicine (Baltimore). 2018; 97:e13886
25. Fernandes RR, Nabuco HCG, Sugihara Junior P, Cavalcante EF, Fabro PMC, Tomeleri CM, et al. Effect of protein intake beyond habitual intakes following resistance training on cardiometabolic
risk disease parameters in pre-conditioned older women. Exp Gerontol. 2018; 110:9–14
26. Soares-Miranda L, Siscovick DS, Psaty BM, Longstreth WT Jr, Mozaffarian D. Physical activity and
risk of coronary heart disease and stroke in older adults: the
cardiovascular health study. Circulation. 2016; 133:147–155
27. Barengo NC, Antikainen R, Borodulin K, Harald K, Jousilahti P. Leisure-time physical activity reduces total and
cardiovascular mortality and
cardiovascular disease incidence in older adults. J Am Geriatr Soc. 2017; 65:504–510
28. Li Y, White K, O’Shields KR, McLain AC, Merchant AT. Light-intensity physical activity and cardiometabolic
risk among older adults with multiple chronic conditions. Am J Health Promot. 2019; 33:507–515
29. Molmen-Hansen HE, Stolen T, Tjonna AE, Aamot IL, Ekeberg IS, Tyldum GA, et al. Aerobic interval training reduces blood pressure and improves myocardial function in hypertensive patients. Eur J Prev Cardiol. 2012; 19:151–160
30. Hwang CL, Yoo JK, Kim HK, Hwang MH, Handberg EM, Petersen JW, Christou DD. Novel all-extremity high-intensity interval training improves aerobic fitness, cardiac function and insulin resistance in healthy older adults. Exp Gerontol. 2016; 82:112–119
31. LaCroix AZ, Bellettiere J, Rillamas-Sun E, Di C, Evenson KR, Lewis CE, et al.; Women’s Health Initiative (WHI). Association of light physical activity measured by accelerometry and incidence of coronary heart disease and
cardiovascular disease in older women. JAMA Netw Open. 2019; 2:e190419
32. Lachman S, Boekholdt SM, Luben RN, Sharp SJ, Brage S, Khaw KT, et al. Impact of physical activity on the
risk of
cardiovascular disease in middle-aged and older adults: EPIC Norfolk prospective population study. Eur J Prev Cardiol. 2018; 25:200–208
33. Wittmann K, Sieber C, von Stengel S, Kohl M, Freiberger E, Jakob F, et al. Impact of whole body electromyostimulation on cardiometabolic
risk factors in older women with sarcopenic obesity: the randomized controlled formosa-sarcopenic obesity study. Clin Interv Aging. 2016; 11:1697–1706
34. Hubbard RE, Searle SD, Mitnitski A, Rockwood K. Effect of smoking on the accumulation of deficits, frailty and survival in older adults: a secondary analysis from the Canadian study of health and aging. J Nutr Health Aging. 2009; 13:468–472
35. Warwick J, Falaschetti E, Rockwood K, Mitnitski A, Thijs L, Beckett N, et al. No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the hypertension in the very elderly trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over. BMC Med. 2015; 13:78
36. Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, et al.; SPRINT Research Group. Intensive vs standard blood pressure control and
cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016; 315:2673–2682
37. Mancia G, Grassi G. Aggressive blood pressure lowering is dangerous: the J-curve: pro side of the arguement. Hypertension. 2014; 63:29–36
38. Bezin J, Moore N, Mansiaux Y, Steg PG, Pariente A. Real-life benefits of statins for
cardiovascular prevention in elderly subjects: a population-based cohort study. Am J Med. 2019; 132:740–748.e7
39. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy in
older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019; 393:407–415
40. Huang ES, Liu JY, Moffet HH, John PM, Karter AJ. Glycemic control, complications, and death in older diabetic patients: the
diabetes and aging study.
Diabetes Care. 2011; 34:1329–1336
41. McNeil JJ, Wolfe R, Woods RL, Tonkin AM, Donnan GA, Nelson MR, et al.; ASPREE Investigator Group. Effect of aspirin on
cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018; 379:1509–1518
42. Bellary S, Sinclair AJ. Manage frailty effectively or manage decline – your choice and responsibility!. Br J Cardiol. 2019; 26
43. Sepehri A, Beggs T, Hassan A, Rigatto C, Shaw-Daigle C, Tangri N, Arora RC. The impact of frailty on outcomes after cardiac surgery: a systematic review. J Thorac Cardiovasc Surg. 2014; 148:3110–3117
44. Krentz AJ, Jacob S. Cardiometabolic medicine: time to recognize a new clinical specialty? Cardiovasc Endocrinol Metab. 2019; 8:47–48
