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Background— There remains limited insight into the pathophysiology and therapeutic advances directed at improving prognosis for patients with heart failure with preserved ejection fraction (HFpEF). Recent studies have suggested a role for coronary microvascular dysfunction in HFpEF. Rb-82 cardiac positron emission tomography imaging is a noninvasive, quantitative approach to measuring myocardial flow reserve (MFR), a surrogate marker for coronary vascular health. The aim of this study was to determine whether abnormalities exist in MFR in patients with HFpEF without epicardial coronary artery disease. Methods and Results— A total of 376 patients with ejection fraction ≥50%, no known history of obstructive coronary artery disease, and a confirmed diagnosis of heart failure (n=78) were compared with patients with no evidence of heart failure (n=298), further stratified into those with (n=186) and without (n=112) hypertension. Global and regional left ventricular MFR was calculated as stress/rest myocardial blood flow using Rb-82 positron emission tomography. Patients with HFpEF were more likely to be older, female, and have comorbid hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, anemia, and renal dysfunction. HFpEF was associated with a significant reduction in global MFR (2.16±0.69 in HFpEF versus 2.54±0.80 in hypertensive controls; P <0.02 and 2.89±0.70 in normotensive controls; P <0.001). A diagnosis of HFpEF was associated with 2.62 times greater unadjusted odds of having low global MFR (defined as <2.0) and remained a significant predictor of reduced global MFR after adjusting for comorbidities. Conclusions— HFpEF, in the absence of known history for obstructive epicardial coronary artery disease, is associated with reduced MFR independent of other risk factors.

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be a renoprotective enzyme, since it converts angiotensin (Ang) II to Ang-(1-7). ACE2 has been detected in urine from patients with chronic kidney disease. We measured urinary ACE2 activity and protein levels in renal transplant patients (age 54 yrs, 65% male, 38% diabetes, n = 100) and healthy controls (age 45 yrs, 26% male, n = 50), and determined factors associated with elevated urinary ACE2 in the patients. Urine from transplant subjects was also assayed for ACE mRNA and protein. No subjects were taking inhibitors of the renin-angiotensin system. Urinary ACE2 levels were significantly higher in transplant patients compared to controls (p = 0.003 for ACE2 activity, and p≤0.001 for ACE2 protein by ELISA or western analysis). Transplant patients with diabetes mellitus had significantly increased urinary ACE2 activity and protein levels compared to non-diabetics (p<0.001), while ACE2 mRNA levels did not differ. Urinary ACE activity and protein were significantly increased in diabetic transplant subjects, while ACE mRNA levels did not differ from non-diabetic subjects. After adjusting for confounding variables, diabetes was significantly associated with urinary ACE2 activity (p = 0.003) and protein levels (p<0.001), while female gender was associated with urinary mRNA levels for both ACE2 and ACE. These data indicate that urinary ACE2 is increased in renal transplant recipients with diabetes, possibly due to increased shedding from tubular cells. Urinary ACE2 could be a marker of renal renin-angiotensin system activation in these patients.

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