Biomarkers and (pre-)diastolic dysfunction in the healthy elderly

Heart failure (HF) is the most common cause for hospitalization and mortality
for subjects older than 65 years. The increased incidence of HF in the elderly
is only in part explained by the increased prevalence of coronary artery
disease and myocardial infarction, hypertension, and diabetes, which all may
result in the development of HF, due to ischemic or hypertensive
cardiomyopathy. However, aging itself also presents a risk factor for
development of HF, specifically because of age-associated fibrosis and
myocardial stiffening leading to HF with preserved ejection fraction (HFpEF).
So, in the upcoming years the burden of HF in the elderly is expected to
increase substantially.

The precise phenotype of *cardiac aging* remains a black box, and early
detection is impossible. We know that cardiac aging appears to be associated
with left ventricular hypertrophy and fibrosis leading to diastolic dysfunction
and subsequent HFpEF (1,2). In HFpEF, left ventricular ejection fraction
(systolic function) and contractility are generally preserved, but myocardial
compliance is compromised (3). As a result, cardiac filling is impaired and
because of this, cardiac output is comprised, especially when additional
triggers are present, such as exercise and atrial fibrillation. Age-related
diastolic dysfunction has a significant impact on the healthy elderly (4). It
limits exercise tolerance and greatly reduces quality of life. Further, as the
aorta also becomes less compliant, an increased pulse pressure with a lower
diastolic pressure may be present, with less ventriculo-aortic reserve and
impaired adaptation to postural changes, causing dizziness and syncope.
Age-related arterial stiffening further increases hemodynamic load,
contributing to the development of cardiomyocyte hypertrophy (5) and leading to
enhanced collagen deposition.

Animal experiments have demonstrated increased collagen deposition in the aging
heart and studies involving human subjects have documented an age-related
increase in cardiac fibrosis. Since increased fibrosis is a major determinant
of increased myocardial stiffness, which together with impaired relaxation
creates the basis for development of diastolic dysfunction, strategies to
detect fibrosis early could be useful to detect age related diastolic
dysfunction. Collectively, accumulating evidence suggests that aging represents
a risk factor for new onset HF, and the link between aging and HF appears to be
primarily myocardial stiffening and fibrosis.

BNP and Galectin-3: Proxy for stretch and fibrosis
B-type natriuretic peptide (BNP) is a 32-amino acid polypeptide secreted by the
ventricles of the heart in response to excessive stretching of heart muscle
cells (cardiomyocytes). Since its discovery over 15 years ago, has emerged as
an important biomarker with an established role in the diagnosis of congestive
heart failure (CHF). Investigators from several large studies examined the
performance characteristics of BNP testing in the acute care setting to assist
in diagnosing CHF and in predicting long-term morbidity and mortality.

Galectin-3 is a carbohydrate binding lectin that is present in the
matricellular space in many organs, including the heart. Galectin-3 has been
shown to be a contributory factor in tissue remodeling and could therefore
function as an intermediate between fibrosis and HF development. In 2004, it
was observed that galectin-3 is the most over-expressed gene in failing hearts
from transgenic hypertensive rats (6).
Hereafter, it was shown in numerous studies that plasma galectin-3 levels are
increased in HF patients, and these levels provide strong prognostic value,
independent from established predictors like age, gender and kidney function
(7). In line with the experimental (rat, mouse) observations (8) that
galectin-3 is co-localized with fibrosis, it has also been observed that
galectin-3 levels relate to markers of matrix turnover (9).

Furthermore, the prognostic importance of plasma galectin-3 levels appears to
be stronger in patients with HF with preserved ejection fraction (HFpEF) (10).

Besides HF, both plasma galectin-3 and BNP levels may also predict outcome in
the general population. Interestingly, both makers predict all-cause mortality
in the general population, the PREVEND study (11). These observations in the
general population provided support for the hypothesis that BNP and galectin-3
may contribute to the early development of cardiovascular disease and HF.

To assess whether elevated galectin-3 and BNP could identify apparently healthy
elderly subjects that are prone to develop diastolic dysfunction compared to
those with low levels, in a case-control study design.

Population-based enrolment will be performed with participants from Lifelines.
These individuals have to be part of the pre-selected Lifelines Deep cohort to
have all the biomarker and genetic data available. To answer the primary
question, 100 subjects with high and low biomarker levels will be invited to
our out-patient clinic for cardiac phenotyping (see flow-chart). Cardiac
phenotyping, consisting of Echocardiography, ECG, EndoPath and blood drawn will
only performed once. These measurements will be finished within 1 year after
METc approval. This is primarily an observational study in which biomarkers
will be assessed in their diastolic dysfunction properties.

Participation will contribute to increasing knowledge about imaging biomarkers
with the final aim to integrate these biomarkers into personalized health
strategies in the general population. Participants will only be informed in
case of any abnormalities, which we anticipate not to discover. All the
measurements performed are non-invasive so bare no to minimal risk. There are
not adverse events expected during the collection of the diastolic phenotyping.