Impaired Global Myocardial Flow Dynamics Despite Normal Left Ventricular Function and Regional Perfusion in Chronic Kidney Disease: A Quantitative Analysis of Clinical ⁸²Rb PET/CT Studies

Abstract

Impaired global myocardial flow reserve (MFR) may be associated with increased risk for cardiac events and coronary artery disease progression. Chronic kidney disease (CKD) is also considered a risk factor for cardiovascular disease. We sought to investigate the effect of CKD on the myocardial microcirculation in patients referred for clinical 82 Rb PET/CT, who had normal left ventricular (LV) function and no flow-limiting coronary artery disease. Methods: Estimated glomerular filtration rate (eGFR) was available for 230 patients who had undergone rest and pharmacologic stress 82 Rb PET/CT for suspected coronary artery disease. CKD was defined as an eGFR less than 60 mL/min/1.73 m 2 . After patients with hemodialysis, a renal transplant, abnormal regional perfusion (summed stress score . 4), or reduced LV function (LV ejection fraction , 45%) were excluded, 40 CKD patients remained. Those were compared with a control group without CKD, which was matched for age, sex, coronary risk factors, and systemic hemodynamics (n 5 42). List-mode acquisition of PET enabled quantification of myocardial blood flow (MBF) and MFR using a previously validated retention model with correction for 82 Rb extraction. Rest MBF was normalized to rate-pressure product. Results: Mean eGFR in the CKD group was reduced (44 6 14 vs. 99 6 28 mL/min/ 1.73 m 2 ; P , 0.0001), and creatinine was significantly elevated, compared with controls (1.9 6 1.1 vs. 0.8 6 0.2 mg/dL; P , 0.0001). MFR was significantly reduced in CKD (2.2 6 1.0 vs. 3.0 6 1.2 for controls; P 5 0.027). This reduction was mainly due to increased rest MBF (1.1 6 0.4 in CKD vs. 0.8 6 0.2 mL/ min/g in controls; P 5 0.007). Stress myocardial flow was comparable between both groups (2.3 6 0.9 vs. 2.3 6 0.8 mL/min/g; P 5 0.08). Overall, MFR was significantly correlated with eGFR (r 5 0.41; P 5 0.0005). Stress MBF did not correlate with eGFR (r 5 0.002; P 5 0.45), but rest MBF showed an inverse correlation (r 5 20.49; P , 0.0001). Rest MBF was also inversely correlated with hemoglobin (r 5 20.28; P 5 0.014), but only eGFR was an independent correlate at multivariate analysis.Conclusion: MFR is impaired in patients with renal insufficiency with normal regional perfusion and LV function, mostly because of elevated rest flow. Absolute quantification of flow may be useful to identify microvascular dysfunction as a precursor of clinically overt coronary disease in this specific risk group.

Reduced Myocardial Flow in Heart Failure Patients With Preserved Ejection Fraction

“…Global MFR has also been studied in patients with renal insufficiency and was noted to be impaired in this population despite normal regional perfusion and left ventricle function. 21 To our knowledge, this is the first study to demonstrate reduced MFR using PET imaging in patients with HFpEF, extending and supporting recent work in this area. In this study, we showed that MFR was significantly lower in HFpEF than in controls, and more pronounced in HFpEF subjects with severe symptomatic HF (NYHA functional class 3-4).…”

“…Previous studies have demonstrated that MFR <2.0 is associated with a significant increase in the risk of cardiac events and death. 11,21,22 In addition to adding pathophysiologic insight into associations of HFpEF, the results of this study justify further research to determine if MFR may represent a novel prognostic risk factor for patients with HFpEF.…”

Fractional Flow Reserve Evaluation and Chronic Kidney Disease: Analysis From a Multicenter Italian Registry (the FREAK Study)

“…Similarly, it has been demonstrated that CKD induces a significant endothelial and microvascular dysfunction . The exact mechanisms by which coronary microcirculation is impaired in renal dysfunction are not fully elucidated . Neurohumoral activation, which is present in CKD, may be one contributor .…”

“…ADMA exerts opposite effects to those of nitric oxide, impairing endothelial function and vasodilatation . Arterial hypertension and chronic anemia, frequently associated with CKD, may also alter vasoreactivity . Despite uncertainties on the mechanism, it is clear that CKD patients have a reduced coronary vasodilator capacity .…”

Quantitative Assessment of Coronary Microvascular Function

“…104, 105, 114, 116 Reduced CFR has been also identified in patients with chronic kidney disease and CFR has been shown to have a significant positive correlation with GFR in these patients. 120 Additionally, global CFR was shown to be independently associated with all-cause mortality in dialysis dependent end stage renal disease patients. 121 Impaired CFR has been also described in a wide variety of chronic autoimmune diseases including rheumatoid arthritis, 122 systemic lupus erythematosus, 123 and systemic sclerosis.…”