Coronary Microvascular Dysfunction and Future
Coronary Microvascular Dysfunction and Future
Coronary Microvascular Dysfunction and Future
Received 14 July 2017; revised 8 October 2017; editorial decision 17 November 2017; accepted 4 December 2017; online publish-ahead-of-print 26 December 2017
See page 850 for the editorial comment on this article (doi: 10.1093/eurheartj/ehx818)
Aims Coronary microvascular ischaemia, cardiomyocyte injury and stiffness may play an important role in the pathophysi-
ology of heart failure with preserved ejection fraction (HFpEF). To date, the relationship between coronary flow
reserve (CFR), myocardial injury, diastolic dysfunction, and future HFpEF risk is unknown.
...................................................................................................................................................................................................
Methods Consecutive patients (n = 201) undergoing evaluation for suspected coronary artery disease (CAD) with stress
and results myocardial perfusion positron emission tomography, serum troponin, and transthoracic echocardiography who did
not have flow-limiting CAD or reduced left ventricular ejection fraction were identified. Patients were followed up
(median 4.1 years) for cardiovascular death and hospitalization for non-fatal myocardial infarction or heart failure.
Coronary flow reserve was quantified as stress/rest myocardial blood flow. Early diastolic flow (E) and relaxation
(e0 ) velocities were obtained via transmitral and tissue Doppler, respectively. Patients with impaired CFR (<2,
n = 108) demonstrated linearly decreasing e0 and increasing E/e0 consistent with worsening diastolic function (P for
trend <0.0001). A detectable troponin was associated with diastolic dysfunction only in the presence of impaired
CFR (interaction P = 0.002). In adjusted analyses, impaired CFR was independently associated with diastolic dysfunc-
tion (E/e0 septal > 15, adjusted OR 2.58, 95%CI 1.22–5.48) and composite cardiovascular outcomes or HFpEF hospi-
talization alone (adjusted HR 2.47, 95%CI 1.09–5.62). Patients with both impaired CFR and diastolic dysfunction
demonstrated >five-fold increased risk of HFpEF hospitalization (P < 0.001).
...................................................................................................................................................................................................
Conclusion In symptomatic patients without overt CAD, impaired CFR was independently associated with diastolic dysfunction
and adverse events, especially HFpEF hospitalization. The presence of both coronary microvascular and diastolic
dysfunctions was associated with a markedly increased risk of HFpEF events.
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Keywords Coronary microvascular ischaemia • Coronary flow reserve • Diastolic dysfunction • Cardiac troponin
• Heart failure with preserved ejection fraction
* Corresponding author. Tel: þ1 617 732 6291, Fax: þ1 617 582 6056, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author 2017. For permissions, please email: [email protected].
HFpEF risk in patients with coronary microvascular dysfunction 841
Diagnostics) with reference range <0.01 mg/L reflecting a 99th percentile .. between impaired CFR and outcome events after controlling for effects
..
cut-off point of less than 0.01 mg/L. Values above the reference range indi- .. of clinically important covariates. Univariate associations were tested and
cated detectable troponin. The peak value from serial assessment for .. Cox models sequentially added pretest clinical score and laboratory and
..
each patient was used. .. imaging variables, with the collinearity index used to check for linear com-
.. binations among covariates, and the Akaike information criterion
Outcomes .. assessed to avoid overfitting. The proportional hazards assumption was
..
Subjects were followed up for a median of 4.1 years (Q1–Q3 1.4–6.6) for .. confirmed with the use of martingale residuals. The final model with
the occurrence of MACE, including cardiovascular death and hospitaliza-
.. impaired CFR and elevated E/e0 was adjusted for pretest clinical score,
..
tion for non-fatal myocardial infarction or heart failure. The date of the .. history of atrial fibrillation, reduced eGFR, detectable troponin, and LVEF.
last consultation was used to determine follow-up. Time to first event .. Interaction terms for CFR and diastolic dysfunction were tested for signif-
..
was analysed. Ascertainment of clinical endpoints was determined by
... icance in the adjusted model.
blinded expert committee adjudication of the integrated electronic longi- .. To further investigate the presence of effect modification between
tudinal medical record, Partners Healthcare Research Patient Data .. coronary microvascular ischaemia and diastolic dysfunction on HFpEF
Registry, the National Death Index, mail surveys, and telephone calls. For
.. outcomes, we performed an exploratory analysis where we stratified
..
a
The P-value is for the comparison between groups and is based on the Fisher’s exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables.
b
Continuous variables are presented as medians (quartile 1–3).
c
Pretest clinical score integrates age, gender, presence of hypertension, dyslipidaemia, diabetes, BMI > 27, oestrogen status, smoking history, family history, and angina history
into a pretest risk score for coronary artery disease: Risk: low (0–8), intermediate (9–15), and high (>15).22
d
Cardiac troponin T or I, as determined by clinically available local assay.
e
Rest myocardial blood flow and coronary flow reserve are corrected for rest rate pressure product (heart rate systolic pressure).
with a detectable troponin (see Supplementary material online, .. modelling incorporating pretest clinical score, age, history of atrial
..
Figure S1). .. fibrillation, reduced eGFR, LVEF, detectable troponin and impaired
In univariable analysis, there was a significant association between
.. CFR, this association remained significant for impaired CFR (odds
..
impaired CFR and elevated E/e0 septal > 15 (odds ratio for CFR < 2, .. ratio 2.58, 95% CI 1.22–5.48, P = 0.01) (Figure 2). Impaired CFR was
3.06, 95% CI 1.56–6.02, P = 0.001). In multivariable logistic regression
.. independently associated with E/e0 septal > 15, a specific non-invasive
844 V.R. Taqueti et al.
marker of elevated cardiac filling pressures, in patients without flow- .. analysis, those patients with elevated E/e0 and impaired CFR experi-
..
limiting CAD. .. enced the highest cumulative rate of HFpEF hospitalization (P < 0.001
.. unadjusted and adjusted for pretest clinical score and detectable tro-
..
Coronary flow reserve, diastolic .. ponin) (Figure 4A and B). The adjusted annualized rate of HFpEF hos-
..
dysfunction, and cardiovascular events .. pitalization in this subgroup was 14.6% when compared with 2–3%
During follow-up over a median of 4.1 years (Q1–Q3, 1.4–6.6 years), .. for all other subgroups (P < 0.001) (Figure 4C). Findings were similar
..
51 patients met the primary composite endpoint of cardiovascular .. for reduced e0 (adjusted for age) and impaired CFR, where CFR fur-
death or hospitalization for non-fatal myocardial infarction or heart
.. ther modified the effect of e0 on future risk of HFpEF hospitalization
..
failure (Table 2). All hospitalization events occurred >30 days follow- .. (P for interaction = 0.03, see Supplementary material online,
ing imaging. These included 36 patients admitted for heart failure, all
..
.. Figure S2). Thus, for the same apparent level of diastolic dysfunction,
in the setting of preserved ejection fraction. In univariable modelling, .. patients with coronary microvascular ischaemia demonstrated a
..
the cumulative rate of MACE or HFpEF hospitalization was signifi- .. greater than five-fold increased risk of HFpEF hospitalization.
cantly associated with impaired CFR (hazard ratio for CFR < 2, 2.86; ..
..
95% CI 1.52–5.41; P = 0.001 for MACE and 3.01; 95% CI 1.41–6.44; ..
P = 0.005 for HFpEF hospitalization). These associations remained .. Discussion
..
significant after the addition of clinically and statistically important ..
covariates into a multivariable model, including pretest clinical score, .. We demonstrate that in symptomatic patients without flow-limiting
.. epicardial CAD, impaired CFR is independently associated with dia-
age, history of atrial fibrillation, reduced eGFR, detectable troponin, ..
LVEF, and E/e0 septal>15 (adjusted hazard ratio for CFR < 2, 2.38; 95% .. stolic dysfunction and adverse cardiovascular outcomes, including
.. HFpEF hospitalization. The latter was observed even after adjustment
CI 1.21–4.67; P = 0.01 for MACE and 2.47; 95% CI 1.09–5.62; P = 0.03 ..
for HFpEF hospitalization) (Table 3). Accordingly, patients with
.. for the presence of detectable myocardial injury and diastolic dys-
..
impaired CFR experienced worse event-free survival in comparison .. function. CFR < 2, here reflecting CMD, was as strongly associated
.. with MACE and HFpEF events as was E/e0 septal > 15, a non-invasive
to those with preserved CFR, in composite MACE (Figure 3A) or ..
HFpEF hospitalization (Figure 3B). Impaired CFR, here reflecting .. echocardiographic marker with high specificity for increased LV filling
.. pressures. After adjusting for clinical covariates and a detectable tro-
CMD, was as strongly associated with MACE and HFpEF events as ..
non-invasive measures of elevated cardiac filling pressures (adjusted .. ponin, we show that the risk of HFpEF was significantly increased
..
hazard ratio for E/e0 septal>15, 2.24; 95% CI 1.18–4.27; P = 0.01 for .. only in those patients with both diastolic dysfunction and impaired
MACE and 2.32; 95% CI 1.09–4.91; P = 0.03 for HFpEF hospitaliza- .. CFR. Finally, we provide evidence via significant interactions for effect
..
tion) (Table 3). .. modification of the association between: (i) myocardial injury and
In an exploratory analysis of the relationship between CFR, dia- .. CMD on diastolic dysfunction, including noninvasive measures of
..
stolic dysfunction, and HFpEF hospitalization, we stratified probability .. impaired cardiac relaxation and elevated filling pressures, and (ii) dia-
of HFpEF hospitalization by CFR and diastolic dysfunction. In stratified
.. stolic function and CMD on future risk of HFpEF hospitalization.
HFpEF risk in patients with coronary microvascular dysfunction 845
Table 3 Association between impaired coronary flow reserve or elevated E/e0 and clinical outcomes
Outcomes Univariable model hazard ratio (95% CI) Multivariable modela hazard ratio (95% CI)
....................................................................
b c
........................................................................
CFR < 2 0
E/e > 15 CFR < 2b E/e0 > 15 c
....................................................................................................................................................................................................................
Cardiovascular death, myocardial 2.86 (1.52–5.41) 3.28 (1.89–5.71) 2.38 (1.21–4.67) 2.24 (1.18–4.27)
infarction, or heart failured
Heart failure with preserved ejection fractiond 3.01 (1.41–6.44) 4.00 (2.07–7.76) 2.47 (1.09–5.62) 2.32 (1.09–4.91)
a
Adjusted for pretest clinical score, history of atrial fibrillation, estimated glomerular filtration rate <60 mlmin-11.73 m-2, detectable troponin, left ventricular ejection fraction,
coronary flow reserve <2 and E/e0 septal > 15.
b
CFR denotes coronary flow reserve <2 relative to >_ 2.
c
E/e0 denotes E/e0 septal > 15 relative to <_ 15.
d
Myocardial infarction or heart failure denotes hospitalization for myocardial infarction or heart failure, respectively. All heart failure hospitalizations occurred in the setting of
preserved ejection fraction.
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