A genome-wide association study meta-analysis of nearly 2 million individuals has linked 66 regions of the genome to the risk of developing specific subtypes of heart failure. The research highlights new genes and disease mechanisms underpinning this common condition.
Heart failure is not a single condition and consists of multiple subtypes defined by the upstream causes and how heart function is affected. People with heart failure are defined clinically according to whether they have reduced or preserved left ventricular ejection fraction. Differentiating between these subtypes is important when investigating new treatments.
A new study reveals that genetic variants influence the risk of developing certain subtypes of heart failure more than others.
The research also highlights that some subtypes are more likely to manifest as multiple-organ diseases involving the kidneys, muscles or pancreas than others.
These findings could influence the approach towards people with heart failure. More deeply understanding these genetic and clinical distinctions can potentially enable the identification of new treatment strategies to improve patient outcomes.
“This improves insight into the underlying disease mechanisms associated with various subtypes of heart failure. While the heart remains the primary organ underlying heart failure with reduced ejection fraction, our analysis reveals that the kidneys and other organs contribute substantially to heart failure with preserved ejection fraction,” explains a researcher behind the study, Tom Lumbers, an Associate Professor and Cardiologist at University College London and University College London Hospitals and Barts Heart Centre, United Kingdom.
The discovery could pave the way for research into treatments that address the multiple-system nature of heart failure rather than focusing solely on the heart.
The research has been published in Nature Genetics.
Genetic data from nearly 2 million individuals
The researchers combined genetic and health data on 1,946,349 individuals from 42 studies across the world, 153,174 of whom had heart failure. They then classified patients according to whether their heart failure was ischaemic or non-ischaemic and whether they had preserved or reduced ejection fraction.
The researchers assessed associations between 10,199,961 genetic variants – small genetic differences that may be associated with increased disease risk – and the likelihood of developing heart failure and its four subtypes
Within the study population, 91% had European ancestry, 6.2% east Asian ancestry, 2.2% African ancestry, 0.5% south Asian ancestry and 0.1% admixed American ancestry. A total of 44,012 individuals had been diagnosed with non-ischaemic heart failure.
66 genetic regions associated with an increased risk of heart failure
This study represents the most comprehensive investigation of the genetic components of subtypes of heart failure.
The researchers identified 56 genetic variants associated with an increased risk of developing any subtype of heart failure and 10 genetic variants linked to an elevated risk of non-ischaemic subtypes of heart failure.
Of the 66 genetic variants identified, 46 were associated with a higher risk of developing at least one non-ischaemic subtype. Meanwhile, 20 genetic variants were linked to an increased risk of heart failure more broadly but not specifically to non-ischaemic heart failure.
Notably, 37 of these genetic variants had not previously been identified as associated with heightened risk of heart failure.
“Our findings enhance the understanding of genetic factors influencing the risk of developing heart failure, including its subtypes. We also found that genetic factors have greater influence on the risk of heart failure with reduced ejection fraction than heart failure with preserved ejection fraction,” says Tom Lumbers.
Genetic risk variants among heart failure subtypes
The researchers further investigated the organs and tissues influenced by these genetic risk variants. Notable differences emerged between the subtypes of heart failure: heart tissue was most important for all heart failure subtypes, except heart failure with preserved ejection fraction, for which the kidney and pancreas were most important.
“These findings provide new evidence supporting the concept that heart failure with preserved ejection fraction is a multiple-organ clinical syndrome and provides insights into the underlying biological mechanisms,” explains Tom Lumbers.
Major studies in progress
The study also used genetic data to estimate the extent to which 24 distinct lifestyle factors influence the risk of heart failure and its subtypes. In particularly, this highlights the effects of smoking and alcohol consumption – modifiable factors that can influence genetic predisposition to heart failure. Understanding these connections is crucial, since it helps to identify lifestyle changes that might reduce the risk of heart disease, motivating future clinical studies.
“This study encourages us to expand our perspective on the causes of heart failure with preserved ejection fraction. It also provides insights to motivate further research,” concludes Tom Lumbers.
He adds that large prospective trials involving thousands of people with heart failure with preserved ejection fraction are already underway in both the United Kingdom and the United States. These trials aim to understand the defining characteristics of this specific subtype of heart failure and to explore the most effective treatment strategies.
