Physicians' Academy for Cardiovascular Education

Coronary microvascular dysfunction may play a role in the pathophysiology of HFpEF

Literature - Kato S et al., J Am Heart Assoc. 2016

Impairment of Coronary Flow Reserve Evaluated by Phase Contrast Cine‐Magnetic Resonance Imaging in Patients With Heart Failure With Preserved Ejection Fraction

 
Kato S, Saito N, Kirigaya H, et al.
J Am Heart Assoc. 2016;5:e002649. First online February 23, 2016. doi: 10.1161/JAHA.115.002649
 

Background

Outcomes for patients with heart failure with preserved ejection fraction (HFpEF) are similar to those with HF with reduced EF (HFrEF) [1,2]. The precise pathophysiological mechanisms underlying HFpEF remain to be elucidated, but is thought to involve diastolic dysfunction [3], myocardial ischaemia, cardiomyocyte hypertrophy, cardiac inflammation [4] and endothelial dysfunction [5,6].
Decreased coronary flow reserve (CFR) has been associated with hypertrophic cardiomyopathy [7], HF [8] and dilated cardiomyopathy [9]. This study tests the hypothesis that CFR is decreased in HFpEF.
CFR was calculated from coronary sinus blood flow measurement by non-contrast phase-contrast (PC) cine-magnetic resonance imaging (cine-MRI). 27 HFpEF patients were prospectively enrolled (2 excluded), 13 with hypertensive left ventricular hypertrophy (LVH), and 18 control subjects.
 

Main results

  • Mean LVEF did not differ significantly between the patient groups (69+7% in HFpEF, 63+6% in hypertensive LVH and 67 +8% in controls). LV mass (LVM) index was 111+36 g/m2 in HFpEF patients, 132+21 g/m2 in hypertensive LVH patients, and 60+26 g/m2 in control subjects.
  • HFpEF patients had lower mean CRF than controls (2.21+0.55 vs. 3.83+0.74, P<0.001), and than the hypertensive LVH group (2.21+0.55 vs. 3.05+0.74, P=0.002).
  • HFpEF patients and hypertensive LVH showed substantially higher rate pressure products (RPP)-corrected coronary sinus blood flow at rest than control subjects. All groups showed a significant increase in coronary sinus blood flow in response to ATP infusion.
    Δ corrected sinus blood flow and CFR were lower in HFpEF patients than in hypertensive LVH patients or in controls (2.21+0.55 in HFpEF; 3.03+0.71 in hypertensive LVH; 3.83+0.73 in control subjects; all P<0.05).
  • CFR impairment (CFR<2.5) occurred more often in HFpEF patients (19 out of 25, 76%) than in hypertensive LVH patients (4 0f 13%, 31%), and controls (0 of 18, 0%).
  • In univariable linear regression analysis, a significant negative correlation was observed between serum BNP and coronary flow reserve (y=-74.3x+362.5;P<0.001). No significant associations were found between serum BNP and EF or E/e’ or LA dimension.
    In multiple regression analyses, CFR was only significantly and independently related to BNP.
 

Conclusion

This study shows, for the first time, reduced CFR in HFpEF patients, as compared with hypertensive LVH patients and controls. CFR was impaired in the majority of HFpEF patients, and decreased CFR is significantly associated with elevated serum BNP concentration.
CFR is considered as a functional measure of epicardial coronary artery and intramyocardial microvessels, and in absence of obstructive stenosis in the epicardial coronary artery, it may be a measure of coronary microvascular dysfunction. These data combined suggest that coronary microvascular dysfunction plays a role in the pathophysiology of HFpEF.
 

Editorial comment [10]

Endothelial dysfunction has been postulated to play a dominant role in the pathophysiology of HFpEF, via a nitric oxide (NO)-dependent route that causes increased myocardial tension attributed to decreased NO bioavailability, and an NO-independent process promoting collagen production and cross-linking. Studies in cardiomyocytes of patients have demonstrated that “oxidative stress and reduced NO bioavailability increases diastolic stiffness through downstream effects on titin.”
(…) “A potential common pathway affecting both stiffness and collagen deposition is that comorbidities contribute to an inflammatory state, resulting in both endothelial dysfunction—resulting in diastolic stiffness—and increased collagen synthesis, leading to fibrosis.” Observations in a recent study of structural changes in full-thickness myocardial autopsy specimens from 124 subjects with HFpEF and 104 controls who died of noncardiac causes, supported “a role of coronary microvascular endothelial inflammation and microvascular rarefaction in the pathophysiology of HFpEF.” The results by Kato et al further indicate that impairment CFR might be a pathophysiological factor of HFpEF development and disease severity progression.
Many questions remain unanswered. ” There is an unmet need to classify HFpEF patients based
on their myocardial vasodilator response as well as characterize their ventricular mechanics, inflammatory and neurohormonal milieu, myocardial substrate, and overall outcomes.” (…) “Identification and classification of HFpEF based on the presence of endothelial or microvascular dysfunction may identify high-risk subgroups that may benefit from therapy targeted to the endothelium and/or microvasculature. In this respect, Kato et al. should be congratulated for their important findings that certainly will move this field forward.”
 
Find this article online at J Am Heart Assoc
 

References

1. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355:260–269.
2. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251–259.
3. Zile MR, Gaasch WH, Anand IS et al. Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-Preserve) trial. Circulation. 2010;121:1393–1405.
4. Paterson I, Michelakis ED. The role of Doppler echocardiography in pulmonary artery hypertension: the importance of proving the obvious. Chest. 2011;139:973–975.
5. Akiyama E, Sugiyama S, Matsuzawa Y, et al. Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol. 2012;60:1778–1786.
6. Ouzounian M, Lee DS, Liu PP. Diastolic heart failure: mechanisms and controversies. Nat Clin Pract Cardiovasc Med. 2008;5:375–386.
7. Kawada N, Sakuma H, Yamakado T, et al. Hypertrophic cardiomyopathy: MR measurement of coronary blood flow and vasodilator flow reserve in patients and healthy subjects. Radiology.
1999;211:129–135.
8. Lund GK, Watzinger N, Saeed M, et al. Chronic heart failure: global left ventricular perfusion
and coronary flow reserve with velocity-encoded cine MR imaging: initial results. Radiology. 2003;227:209–215.
9. Watzinger N, Lund GK, Saeed M et al. Myocardial blood flow in patients with dilated cardiomyopathy: quantitative assessment with velocity-encoded cine magnetic resonance imaging of the coronary sinus. J Magn Reson Imaging. 2005;21:347–353.
10. Giamouzis G. Schelbert EB, Butler J. Growing Evidence Linking Microvascular Dysfunction With Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc. 2016;5:e003259 doi: 10.1161/JAHA.116.003259