Heart and vessels ‘on fire’

Inflammation is a crucial response towards infections and has been determinant for the conservation of our species throughout the millennia. However, the low grade, chronic and sterile activation of such a process seen during ageing (also known as ‘inflammaging’) is a pillar of the pathophysiology of many cardiovascular (CV) afflictions of the elderly including coronary heart disease, heart failure and arrhythmias.1 Furthermore, the association between inflammation and atherosclerotic disease (30302102), type 2 diabetes mellitus (31656034) or obesity is well established. As a result, inflammation represents a possible target for the development of cardioprotective therapies as shown in recent randomized controlled trials.2 Several pathways contribute to the development and maintenance of a proinflammatory state, including metabolism, lifestyle, environmental and genetic factors (Figure 1). Genetic accounts for up to 55% of variation of plasma inflammatory molecules.3 Studies from centenaries found all over the world, such as in Sardinia (Italy) or Okinawa (Japan) islands, confirmed the role of a favourable genetic background on CV ageing. However, while a good genetic certainly helps in favouring healthiness, also the ‘context’ in which the genetic expression takes place can differ significantly impacting on disease onset and progression. Unhealthy lifestyles lead to CV diseases (CVD) through several mechanisms including epigenetic regulation of inflammatory gene expression.4 As well known, excess of weight, active smoke, sedentarism and unhealthy diets are crucial risk factors for CV health. The relation between metabolism and CV health is far from being linear and fully described. The socalled metabolically healthy obesity phenotype (i.e. obesity paradox) with the excess of weight counterintuitively favouring a safer CV profile in certain conditions is a good example.5 The metabolic profile (including lipid, insulin and inflammatory factors) may be the real determinant of CV condition and certain obese individuals may have a protective metabolic profile while living with excess of weight. On the opposite, normal weight individuals or even sarcopenic individuals may show features of adverse metabolism and living with a higher CV risk. As a consequence, while reducing the weight of a subject might be a good preventive strategy, paying more attention to the presence of dysmetabolism is even more crucial. To this end, regular physical activity ameliorates the metabolic status through increasing insulin sensitivity or reducing proprotein convertase subtilisin/kexin type 9 (PCSK9) levels with direct effect on CV prevention.6 Again, both insulin resistance and increased levels of circulating lipids have been associated with lowgrade inflammation. Accordingly, an impaired metabolism is among the main causes of the chronic inflammation found in elderly subjects. Altered glucose and lipid metabolism together with an excess of dysfunctional and inflamed adipose tissue associates with a reduction of antiinflammatory adipokines (i.e. adiponectin and omentin) and an increase of proinflammatory molecules (such as leptin, interleukin1β, interleukin6 and tumour necrosis factor alpha)