Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2 diabetes mellitus

Abstract

Aims: Patients with type 2 diabetes mellitus (T2DM) are known to have impaired resting myocardial energetics and impaired myocardial perfusion reserve, even in the absence of obstructive epicardial coronary artery disease (CAD). Whether or not the pre-existing energetic deficit is exacerbated by exercise, and whether the impaired myocardial perfusion causes deoxygenation and further energetic derangement during exercise stress, is uncertain.

Methods and results: Thirty-one T2DM patients, on oral antidiabetic therapies with a mean HBA1c of 7.4 ± 1.3%, and 17 matched controls underwent adenosine stress cardiovascular magnetic resonance for assessment of perfusion [myocardial perfusion reserve index (MPRI)] and oxygenation [blood-oxygen level-dependent (BOLD) signal intensity change (SIΔ)]. Cardiac phosphorus-MR spectroscopy was performed at rest and during leg exercise. Significant CAD (>50% coronary stenosis) was excluded in all patients by coronary computed tomographic angiography. Resting phosphocreatine to ATP (PCr/ATP) was reduced by 17% in patients (1.74 ± 0.26, P = 0.001), compared with controls (2.07 ± 0.35); during exercise, there was a further 12% reduction in PCr/ATP (P = 0.005) in T2DM patients, but no change in controls. Myocardial perfusion and oxygenation were decreased in T2DM (MPRI 1.61 ± 0.43 vs. 2.11 ± 0.68 in controls, P = 0.002; BOLD SIΔ 7.3 ± 7.8 vs. 17.1 ± 7.2% in controls, P < 0.001). Exercise PCr/ATP correlated with MPRI (r = 0.50, P = 0.001) and BOLD SIΔ (r = 0.32, P = 0.025), but there were no correlations between rest PCr/ATP and MPRI or BOLD SIΔ.

Conclusion: The pre-existing energetic deficit in diabetic cardiomyopathy is exacerbated by exercise; stress PCr/ATP correlates with impaired perfusion and oxygenation. Our findings suggest that, in diabetes, coronary microvascular dysfunction exacerbates derangement of cardiac energetics under conditions of increased workload.

Keywords: Coronary microvascular function; Diabetes mellitus; Diabetic cardiomyopathy; Metabolism; Oxygen.

Figure 1

Timeline for scan protocol. Cardiac ³¹P-MRS (3 T) was performed first at rest (9 min) and then during 9 min of leg exercise lying prone, with 2.5 kg weights attached to both legs. This was followed by CMR scan (3 T). CMR included pilot and cine imaging to assess LV volumes, mass, and ejection fraction; myocardial tagging imaging at horizontal long axis; and three ventricular SA slices (basal, mid, and apical LV). For oxygenation-sensitive CMR (BOLD-CMR), three ventricular SA slices (basal, mid, and apical) were acquired at rest. Adenosine (140 µg/kg/min) was then infused for at least 3 min, and the same three BOLD images were acquired during stress. Subsequently, a 0.03 mmol/kg bolus of gadolinium-based contrast (Gadoterate meglumine, Dotarem, Guerbet LLC) was injected for first-pass perfusion imaging. Adenosine was then discontinued; after 10 min of break from scanning, SA stack images were obtained, with the heart rate returned to baseline rest measurements. After at least 20 min to allow adenosine and gadolinium contrast washout, another (second) 0.03 mmol/kg bolus of gadolinium was given for post-adenosine rest perfusion imaging. A third bolus of 0.09 mmol/kg gadolinium was then given for LGE to exclude fibrosis.

Figure 2

Column graphs with means and standard deviations showing differences in rest and exercise myocardial PCr/ATP ratios between controls and patients with T2DM. Bars show mean PCr/ATP ratios and error bars indicate standard deviations.

Figure 3

Representative rest and exercise ³¹P-MR spectra examples. Rest and exercise myocardial phosphorus spectra in a healthy volunteer (top row) and a patient with T2DM. Note a further decrease in already lower rest PCr/ATP in the patient with T2DM during exercise.

Figure 4

Column graphs with means and standard deviations showing differences in MPRI and BOLD SI (%) change between controls and patients with T2DM. Bars show mean PCr/ATP ratios and error bars indicate standard deviations.

Figure 5

Representative CMR perfusion and oxygenation examples. Oxygenation and corresponding perfusion images in a healthy volunteer (top row) and a patient with T2DM. Perfusion reserve (mean MPRI) and oxygenation SIΔ (BOLD SIΔ) were impaired in the patient.