Student:
Evie Templeton
Project:
Genes that predict outcome in heart failure
Supervisors:
Dr Anna Pilbrow and Professor Vicky Cameron
Sponsor:
Canterbury Medical Research Foundation and Mr Roland Stead
Introduction:
Heart failure is a condition which occurs when the heart is unable to pump enough blood
around the body to satisfy its metabolic demands and it is estimated that one in five adults
over 40 will develop this condition. In some cases, the heart cannot fill with enough blood,
whereas in others, the heart can't send blood to the rest of the body with enough force.
Common causes include a long-term high blood pressure or previous heart attack, but it is a
complex trait with a significant inherited component. New genetic risk markers for heart
failure onset and progression have been identified in recent genome-wide association
studies, but it is unknown yet whether these new genetic markers provide additional
predictive information in heart failure patients independent of the established risk factors
such as older age, or elevated circulating heart hormone levels.
To investigate this question, a recent pilot study was conducted by the supervisor for this
project, Dr Anna Pilbrow in a small group of heart failure patients, which identified four risk
markers associated with poor clinical outcome that were independent of established risk
factors.
Aim:
The project aimed to validate these findings in a larger group of heart failure patients over
five years of follow-up and determine whether the genetic risk markers are indeed
independent of the established clinical risk factors.
Method:
DNA samples were collected from a larger, independent cohort of 890 heart failure patients.
To determine whether the patients had the common or rare form of each of the four genes,
DNA samples were genotyped using commercial Taqman real time PCR assays. To determine
if the genotypes were independently associated with clinical outcomes, genotype data was
analysed for association with patient outcomes (mortality, hospital admissions) and clinical
characteristics, adjusting for established risk factors (age, gender, ethnicity, prior heart
attack, diabetes, heart hormones and drug treatments).
Results:
I was able to confirm a previous association between the genetic variant rs2234962 and a
lower risk for developing heart failure, which was indicated by an association with older age
at admission and better cardiac function. However, although my supervisor had seen an
association with greater mortality in the pilot study, I found no association with mortality in
this larger cohort.
Moreover, while my supervisor’s pilot study indicated that the other three genetic variants
were associated with increased heart failure mortality, I found in this more recent cohort that
there was no association with mortality of any of the three genetic variants.
Conclusion:
At first these results seemed unexpected, but we hypothesised that they could be due to the
10-year time gap between collection of samples for each cohort. During this time, there have
been improvements in heart failure management, especially the widespread use of BNPguided treatment. BNP is a heart hormone released when the heart is under stress and by
monitoring the levels of this, clinicians can optimise treatment for patients and improve
survival.
Therefore, the lack of association between genotype and mortality in the validation cohort
could be due to these recent improvements in heart failure management overwhelming the
effects of the genes themselves.
The discovery of new genetic markers for heart failure could help clinicians identify high-risk
patients who may benefit from more intensive treatment. Although we have validated one
genetic marker associated with a protective effect for heart failure, three genetic variants
previously associated with poor survival will not be clinically useful for improving risk
prediction in heart failure.
Thus the search for new genetic markers goes on and could ultimately improve survival in
heart failure patients and reduce the number and duration of hospital admissions for this
condition. As heart failure consumes approximately 2% of New Zealand’s health budget, this
could also help reduce this significant financial burden on the health system.