DISCUSSION
This study evaluated the association between MBFR, a measure of coronary
microvascular function and LV diastolic function, measured via septal
mitral annular E/e’ in a group of patients presenting with chest pain
and unobstructed coronary arteries. Our study showed that there was no
association found between MBFR and LV diastolic function in both
univariate and multivariate regression analysis after taking traditional
cardiovascular risk factors into account.
Contrary to the findings from Taqueti,4 we did not
find any correlation between septal mitral annular E/e’ and MBFR. In
their study, they included patients with a similar profile (patients
presenting with chest pain and no evidence of flow limiting coronary
artery disease (CAD) on PET) yet found that impaired coronary flow
reserve (CFR) in these patients was independently associated with
diastolic dysfunction.4 In addition, they also used a
similar echocardiographic definition for LV diastolic dysfunction to our
study (E/e’ septal>15) and demonstrated a significant
direct relationship between CFR and septal e’ and an inverse
relationship between CFR and E/e’ septal. Their findings were clinically
important as those patients with evidence of both CMD and elevated
septal E/e’ ratio had a five-fold increased risk for HFpEF
hospitalisation after a median follow up of 4 years.4In our study, only 5 out of the 55 (9%) patients with CMD had evidence
of raised LV filling pressures. It is not clear from the study by
Taqueti how many patients with CMD also had echocardiographic evidence
of elevated LV filling pressures (septal mitral annular E/e’ ratio ≥
15), although the published median and quartiles for E/e’ were 13.0
(9.3-16.1) in patients with CMD vs 10.8 (8.7-12.8) in patients without
CMD.4
A larger prospective multicenter study by Shah enrolled 202 patients
with a confirmed diagnosis of HFpEF and measured the prevalence of CMD
via left anterior descending artery Doppler flow signals at rest and
during adenosine infusion.11 CMD was present in nearly
75% of patients and associated with abnormal longitudinal myocardial
function assessed by TTE. However, the main limitation of their study
was the lack of exclusion of macrovascular CAD which would have led to a
lower measurement of CFR. 11,12
There are several potential reasons that might explain the discrepancy
between the findings in our study and previous studies. Firstly, in the
study by Taqueti, their patient cohort included a greater proportion of
comorbidities known to affect both coronary microvascular function and
myocardial stiffness.4 The difference between their
study population and ours were the higher numbers of the patients who
were elderly (median age of 66 vs 59.7), proportions female (64.7% vs
48%), hypertensive (75.6% vs 39%) and had diabetes mellitus (32.8%
vs 11%).4 Additionally, it is possible that despite
the presence of CMD, our patient cohort with its lower prevalence of
co-morbidities, may be earlier on the spectrum of myocardial stiffness
and not yet manifesting detectable diastolic
dysfunction.11,12
Notably, approximately 25% of patients who met the criteria for HFpEF
in the study by Shah did not have evidence of CMD.11This is interesting as it could be explained by the heterogenous nature
of HFpEF driven by non-cardiac specific causes of fluid overload, and
that besides endothelial dysfunction, there may be other factors causing
HFpEF syndrome in these patients.11 This implies that
the presence of CMD does not necessarily equate to the reduction of
diastolic function, hence the absence of correlation between CMD and LV
diastolic function in our study.
The main question of the causal mechanistic links of whether 1) CMD
leads to LV diastolic dysfunction and subsequently HFpEF or 2) LV
diastolic dysfunction observed in patients with HFpEF leads to CMD,
remains unclear. As alluded to, it is possible that our patient cohort
is at an early stage of CMD, prior to the development of diffuse
myocardial fibrosis and subsequent increase in LV stiffness via
recurrent micro-infarctions secondary to coronary microvascular
ischaemia.13 This hypothesis is supported by the
finding of an exacerbated diastolic dysfunction when there was a
detectable troponin in Taqueti’s study.4,13 Limited by
the retrospective nature of this study, it would be interesting to
observe prospectively how many of our patients with CMD eventually
developed evidence of LV diastolic dysfunction or HFpEF.
Previous studies have also postulated that CMD is a consequence of a
systemic pro-inflammatory state which occurs in medical conditions such
as diabetes or obesity.1,6,7,14 Higher levels of
Hs-CRP have also been observed in patients with HFpEF than in patients
with heart failure with reduced ejection fraction (HFrEF), supporting a
link between inflammation and HFpEF.7 However, in our
study, we did not find an association between reduced MBFR and raised
Hs-CRP. This potentially is a result of a lower prevalence of medical
co-morbidities in the patients recruited in our study.