Frail people were more likely to develop heart disease, and a blood "fingerprint" covered part of the link

Frailty is the state in which the body has lost much of its reserve: people tire easily, walk slowly, have a weak grip and may lose weight without trying. Frail older people are known to be more likely to develop heart disease. What sits between the two is less clear. A team at Peking Union Medical College Hospital in Beijing looked for clues in the blood of more than 100,000 British adults.

They found that frailty went with a broad shift in blood chemistry, and that a "signature" built from 36 blood substances accounted, in statistical terms, for about 18.5% of the link between frailty and later coronary artery disease, the narrowing of the arteries that feed the heart muscle. Because the study observes people rather than changing anything, it cannot show that frailty or these substances cause heart disease.

What they did

The data came from UK Biobank, a large British health study that recruited people between 2006 and 2010. The analysis included 223,907 participants who did not have coronary artery disease at the start; their average age was about 57, and 56% were women. They were followed for a median of almost 15 years through hospital, primary care and death records.

Frailty was scored with a widely used five-point checklist: unintended weight loss, exhaustion, slow walking pace, weak grip strength and low physical activity. People with three or more signs counted as frail, those with one or two as "pre-frail". Only 0.8% were frail and about 29% pre-frail, which reflects a mostly middle-aged group.

In 122,959 participants, a technique called NMR (nuclear magnetic resonance) had measured 169 substances in a single blood sample: fats and the particles that carry them, amino acids (the building blocks of protein), sugar-related molecules and an inflammation marker. The team checked which of these went with frailty, then used a statistical method to boil them down to a signature of 36 substances. They also used each person's genetic risk score for coronary artery disease, a number that sums up many small DNA variants linked to the disease.

The results were adjusted for age, sex, education, income, deprivation, body weight, smoking, alcohol, diet, sleep, use of cholesterol-lowering drugs and the number of long-term illnesses.

What they found

• Frailty and heart disease. About 7.8% of participants developed coronary artery disease during follow-up (17,551 people). Compared with people showing no signs of frailty, the risk was about 25% higher in pre-frail people and about 78% higher in frail people. Of the five signs, slow walking showed the strongest link.
• Blood chemistry shifts with frailty. Frailty scores were linked to 162 of the 169 substances, mostly to lower levels. Among the substances that pushed the signature up were certain fats and GlycA, a marker of inflammation; omega-3 and linoleic fatty acids and albumin, a protein often low in poor nutrition, pushed it down.
• The signature and the heart. People in the top fifth of the signature had about 65% higher risk of coronary artery disease than those in the bottom fifth. Statistically, the signature accounted for about 18.5% of the frailty–heart disease link.
• Genes changed the picture. The link between frailty and heart disease was relatively stronger in people with lower genetic risk. People with both high genetic risk and a high signature had the highest risk of all, about 3.5 times that of people low on both.
• Robust to checks. The results held when the team left out people diagnosed in the first two years, people with any heart or blood vessel disease at the start, and when they accounted for people who died of something else first.

What to keep in mind

• Links, not causes. Frailty and blood chemistry were measured at the same single visit, so their order in time is unknown. The authors state plainly that "causal mediation cannot be inferred".
• Other health problems. Illnesses, inflammation and treatments can affect frailty, blood chemistry and heart risk all at once, and may not be fully captured by the adjustments.
• An adapted frailty score. Frailty was measured with the information UK Biobank had, partly from questionnaires, rather than with the original procedures.
• Many people left out. A large share of UK Biobank was excluded, mainly because frailty data were missing, and those included differed somewhat in education and income from those left out.
• Interpretations are tentative. What each blood substance means biologically was drawn from earlier research, not tested here, and the genetic interactions are statistical, not proof of a biological interaction.

Why it matters

Frailty is often treated as a problem of muscles and stamina, while heart disease is seen as a problem of arteries and cholesterol. This study suggests the two share part of their background in the blood: in nutrition, inflammation and fat metabolism. The authors conclude that looking at frailty, blood chemistry and genes together may give a fuller picture of heart risk in later life. Whether changing any of these blood substances would lower anyone's risk is a question this kind of study cannot answer.