Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis

Abstract

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR. METHODS: Ninety-five patients with severe AS without coronary artery disease awaiting AVR (30 AS-T2D and 65 AS-noT2D) were recruited (71 years of age [69, 73]; 34 [37%] women). Thirty demographically matched healthy volunteers (HVs) and 30 patients with T2D without AS (T2D controls) were controls. One month before and 6 months after AVR, cardiac PCr/ATP, adenosine stress MBF, global longitudinal strain, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and 6-minute walk distance were assessed in patients with AS. T2D controls underwent identical assessments at baseline and 6-month follow-up. HVs were assessed once and did not undergo 6-minute walk testing. RESULTS: Compared with HVs, patients with AS (AS-T2D and AS-noT2D combined) showed impairment in PCr/ATP (median [interquartile range]; HVs, 2.15 [1.89, 2.34]; AS, 1.66 [1.56, 1.75]; P <0.0001) and vasodilator stress MBF (HVs, 2.11 mL min g [1.89, 2.34]; AS, 1.54 mL min g [1.41, 1.66]; P <0.0001) before AVR. Before AVR, within the AS group, patients with AS-T2D had worse PCr/ATP (AS-noT2D, 1.74 [1.62, 1.86]; AS-T2D, 1.44 [1.32, 1.56]; P =0.002) and vasodilator stress MBF (AS-noT2D, 1.67 mL min g [1.5, 1.84]; AS-T2D, 1.25 mL min g [1.22, 1.38]; P =0.001) compared with patients with AS-noT2D. Before AVR, patients with AS-T2D also had worse PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.66 [1.56, 1.75]; P =0.04) and vasodilator stress MBF (AS-T2D, 1.25 mL min g [1.10, 1.41]; T2D controls, 1.54 mL min g [1.41, 1.66]; P =0.001) compared with T2D controls at baseline. After AVR, PCr/ATP normalized in patients with AS-noT2D, whereas patients with AS-T2D showed no improvements (AS-noT2D, 2.11 [1.79, 2.43]; AS-T2D, 1.30 [1.07, 1.53]; P =0.0006). Vasodilator stress MBF improved in both AS groups after AVR, but this remained lower in patients with AS-T2D (AS-noT2D, 1.80 mL min g [1.59, 2.0]; AS-T2D, 1.48 mL min g [1.29, 1.66]; P =0.03). There were no longer differences in PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.51 [1.34, 1.53]; P =0.12) or vasodilator stress MBF (AS-T2D, 1.48 mL min g [1.29, 1.66]; T2D controls, 1.60 mL min g [1.34, 1.86]; P =0.82) between patients with AS-T2D after AVR and T2D controls at follow-up. Whereas global longitudinal strain, 6-minute walk distance, and NT-proBNP all improved after AVR in patients with AS-noT2D, no improvement in these assessments was observed in patients with AS-T2D. CONCLUSIONS: Among patients with severe AS, those with T2D demonstrate persistent abnormalities in myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function after AVR; AVR effectively normalizes myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function in patients without T2D.

Myocardial scar and remodelling predict long-term mortality in severe aortic stenosis beyond 10 years

“…We also show that T2DM is independently associated with outcome, its importance more apparent for CV mortality in the subgroup undergoing SAVR (I i for T2DM of 14%, greater than age). T2DM is known to be associated with an increased risk of heart failure, persistent impairment of myocardial energetics, and myocardial perfusion after AVR; 8 dedicated trials of novel diabetic medications in this patient group should therefore be considered. We have previously shown that female sex was associated with CV mortality; 4 this effect remains significant with extended follow-up.…”

Myocardial transcriptomic analysis of diabetic patients with aortic stenosis: key role for mitochondrial calcium signaling

“…In the context of AS, an association between altered myocardial energetics, i.e. reduced PCr/ATP ratios, and contractile dysfunction have been reported in T2D patients [ 17 , 38 , 39 ] . However, the underlying molecular mechanisms leading to this reduced ATP production in the human diabetic heart under chronic pressure overload remained unclear.…”

“…At pre-clinical level, we reported that insulin resistance induced by a high-fat diet in mice worsened survival, cardiac hypertrophy and systolic/diastolic dysfunction under aortic constriction [ 16 ]. In patients with AS, T2D has been associated to a higher cardiomyocyte resting tension, an increased vascular advanced glycation end product deposition [ 14 ], an impaired myocardial energetics as reflected by the reduced phosphocreatine to ATP ratio [ 17 ], oxidative stress and metabolic dysfunction [ 18 ]. Altogether, these data suggest a strong role for metabolic alterations in the deleterious effect of T2D on LV remodeling and function in patients with severe AS.…”

Maintaining energy provision in the heart: the creatine kinase system in ischaemia–reperfusion injury and chronic heart failure

“…Most studies have been performed in highly selective, homogenous, patient groups, but energetic changes also occur in many morbidities that are associated with increased risk of developing heart failure. For example, PCr/ATP is reduced in LVH [ 87 ], atrial fibrillation [ 107 ], aortic stenosis [ 108 ], obesity [ 109 , 110 ] and in Type 2 diabetes [ 111 , 112 ]. In one notable preclinical study, it was found that diabetic mice were relatively protected from heart failure induced by pressure overload and this was attributed to restoring flexibility in energy substrate utilisation [ 113 ].…”