Increase In Myocardial Blood Flow Research Articles

Early signs of myocardial systolic dysfunction in patients with type 2 diabetes are strongly associated with myocardial microvascular dysfunction independent of myocardial fibrosis: a prospective cohort study

BackgroundPatients with diabetes demonstrate early left ventricular systolic dysfunction. Notably reduced global longitudinal strain (GLS) is related to poor outcomes, the underlying pathophysiology is however still not clearly understood. We hypothesized that pathophysiologic changes with microvascular dysfunction and interstitial fibrosis contribute to reduced strain.Methods211 patients with type 2 diabetes and 25 control subjects underwent comprehensive cardiovascular phenotyping by magnetic resonance imaging. Myocardial blood flow (MBF), perfusion reserve (MPR), extracellular volume (ECV), and 3D feature tracking GLS and global circumferential (GCS) and radial strain (GRS) were quantified.ResultsPatients (median age 57 [IQR 50, 67] years, 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. Compared to control subjects GLS, GCS, and GRS were reduced in the total diabetes cohort, and GLS was also reduced in the sub-group of patients without diabetic complications compared to control subjects (controls − 13.9 ± 2.0%, total cohort − 11.6 ± 3.0%; subgroup − 12.3 ± 2.6%, all p < 0.05). Reduced GLS, but not GCS or GRS, was associated with classic diabetes complications of albuminuria (UACR ≥ 30 mg/g) [β (95% CI) 1.09 (0.22–1.96)] and autonomic neuropathy [β (95% CI) 1.43 (0.54–2.31)] but GLS was not associated with retinopathy or peripheral neuropathy. Independently of ECV, a 10% increase in MBF at stress and MPR was associated with higher GLS [multivariable regression adjusted for age, sex, hypertension, smoking, and ECV: MBF stress (β (95% CI) − 0.2 (− 0.3 to − 0.08), MPR (β (95% CI) − 0.5 (− 0.8 to − 0.3), p < 0.001 for both]. A 10% increase in ECV was associated with a decrease in GLS in univariable [β (95% CI) 0.6 (0.2 to 1.1)] and multivariable regression, but this was abolished when adjusted for MPR [multivariable regression adjusted for age, sex, hypertension, smoking, and MPR (β (95% CI) 0.1 (− 0.3 to 0.6)]. On the receiver operating characteristics curve, GLS showed a moderate ability to discriminate a significantly lowered stress MBF (AUC 0.72) and MPR (AUC 0.73).ConclusionsMyocardial microvascular dysfunction was independent of ECV, a biomarker of myocardial fibrosis, associated with GLS. Further, 3D GLS could be a potential screening tool for myocardial microvascular dysfunction. Future directions should focus on confirming these results in longitudinal and/or interventional studies.

Serial fractional flow reserve, coronary flow reserve and index of microcirculatory resistance after percutaneous coronary intervention in patients treated for stable angina pectoris assessed with PET.

Cardiac 15 O-water PET is a noninvasive method to evaluate epicardial and microvascular dysfunction and further quantitate absolute myocardial blood flow (MBF). The aim of this study was to assess the impact of revascularization on MBF and myocardial flow reserve (MFR) assessed with 15 O-water PET and invasive flow and pressure measurements. In 21 patients with single-vessel disease referred for percutaneous coronary intervention (PCI), serial PET perfusion imaging and fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were performed during PCI and after 3 months. In the affected myocardium, stress MBF and MFR increased significantly from before revascularization to 3 months after revascularization: stress MBF 2.4 ± 0.8 vs. 3.2 ± 0.8; P < 0.001 and MFR 2.5 ± 0.8 vs. 3.4 ± 1.1; P = 0.004. FFR and CFR increased significantly from baseline to after revascularization and remained stable from after revascularization to 3-month follow-up: FFR 0.64 ± 0.20 vs. 0.91 ± 0.06 vs. 0.91 ± 0.07; P < 0.001; CFR 2.4 ± 1.2 vs. 3.6 ± 1.9 vs. 3.6 ± 1.9; P < 0.001, whereas IMR did not change significantly: 30.3 ± 22.9 vs. 30.1 ± 25.3 vs. 31.9 ± 25.2; P = ns. After revascularization, an increase in stress MBF was associated with an increase in FFR ( r = 0.732; P < 0.001) and an increase in MFR ( r = 0.499; P = 0.021). IMR measured before PCI was inversely associated with improvement in stress MBF, ( r = -0.616; P = 0.004). Recovery of myocardial perfusion after PCI was associated with an increase in FFR 3 months after revascularization. Microcirculatory dysfunction was associated with less improvement in myocardial perfusion.

Relationship between myocardial strain, coronary microvascular dysfunction, and myocardial extracellular volume in patients with type 2 diabetes: a cross-sectional CMR study

Abstract Background Patients with diabetes often develop heart failure with preserved ejection and often demonstrate early indications of myocardial dysfunction by decreased strain, notably the global longitudinal (GLS). The underlying myocardial phenotypical changes in patients with diabetes are coronary microvascular dysfunction and myocardial interstitial fibrosis. The relation of these to strain-indicators of early systolic dysfunction is not established. Purpose We hypothesized that coronary microvascular function and interstitial fibrosis contribute to the subclinical myocardial dysfunction seen in patients with diabetes. Method With gadolinium contrast and adenosine-stress magnetic resonance imaging, we determined myocardial blood flow (MBF) and perfusion ratio (MPR) and extracellular volume (ECV; an imaging biomarker of diffuse fibrosis) in 211 patients with type 2 diabetes without macrovascular coronary artery disease and 25 control subjects. Left ventricular (LV) function was determined from its ejection fraction and 3D feature tracking of GLS, circumferential (GCS), and radial strains (GRS). Results Without a significant age- or sex-differences to control subjects, patients (median age 57 years [IQR 50, 67], 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. LV ejection fraction was normal and similar to controls. Compared to control subjects (GLS -13.9±2.0%), GLS, GCS and GRS were reduced in the total diabetes cohort, and GLS was reduced also in the subgroup of patients without any diabetes complications (total -11.6±3.0%; without-complications -12.3±2.6%). GLS, but not GCS or GRS or LVEF, was associated with albuminuria (b (95%CI) 1.09 (0.22-1.96)) and autonomic neuropathy (b (95%CI) 1.43 (0.54-2.31)). Independently of ECV, a 10% increase in MBF at adenosine-stress and MPR was associated with improved GLS in uni- and multivariable regression analyses. A 10% increase in ECV was associated with a decrease in GLS in univariable and multivariable regression analysis, but this was abolished when adjusted for MPR. GLS showed a moderate ability to discriminate a significantly lowered myocardial blood flow at stress defined as &amp;lt;1.49 mL/min/g (AUC 0.72, GLS threshold -11.5%; sensitivity 75% and specificity 53%) and myocardial perfusion ratio defined as as &amp;lt;2.1 (AUC 0.73, GLS threshold -10.8% resulted in a sensitivity of 71% and a specificity of 70%). GLS had a poor ability to predict increased extracellular volume defined as &amp;gt; 31% (AUC 0.60, GLS threshold -13.5 resulted in a sensitivity of 72% and a specificity of 34%). Conclusion Of the two important phenotypical changes seen with type 2 diabetes, microvascular dysfunction and fibrosis, coronary microvacular dysfunction demonstrates the more important relation to early systolic compromise as determined from the left ventricle global longitudinal strain.Associations of Systolic parametersROC curve

Abstract 13882: Myocardial Hypoperfusion in Severe Aortic Stenosis is Reversed by Aortic Valve Replacement

Background: Myocardial hypoperfusion in severe aortic stenosis (AS) without obstructive coronary disease may be secondary to hemodynamic influences (and therefore readily reversible by aortic valve replacement[AVR]) or structural alterations in the left ventricle (LV) such as increased mass and reduction in capillary density. Aim: To evaluate the early effect of AVR on myocardial blood flow (MBF) in patients with severe symptomatic AS without flow-limiting coronary artery disease. Methods: Prospective case-control study of severe symptomatic AS without obstructive coronary disease referred for surgical or transcatheter AVR and propensity matched to a control cohort with unobstructed coronary arteries. Patients underwent adenosine stress cardiovascular magnetic resonance at baseline and 8-weeks (median) post-operatively. Histology from 9 myocardial septal biopsies taken at AVR were compared against necropsy controls (n=5). Results: 52 patients were included; 26 with severe AS (median [IQR] age 71[66-75], 73% male) and 26 age, sex and co-morbidity matched controls. In AS, peak velocity(Vmax) was 4.3m/s[4.1-4.5] and AVA 0.8cm 2 [0.6-0.9]. AS patients had greater LV mass and late gadolinium enhancement. AS patients had lower stress MBF than controls (1.63ml/g/min[1.38-2.08] vs 2.13[1.76-2.52], p=0.003) which increased to 1.97ml/g/min after AVR (p=0.7 post-AVR vs. Controls). This was driven by a 40% increase in subendocardial MBF (1.26ml/g/min[1.18-1.78] to 1.77[1.62-2.32]). Capillary density was reduced almost threefold in AS (495/mm 2 [407-686] vs 1376[1208-1579], p&lt;0.001). Conclusions: Severe AS results in subendocardial hypoperfusion which is rapidly improved after AVR. There is a threefold reduction in capillary density, however factors related to elevated afterload (which is reduced by AVR) are the most influential.

99-LB: Myocardial Blood Flow in Association with Baseline Ejection Fraction after Elevation in Plasma Ketones in Patients with T2DM and Heart Failure

Background: SGLT2 inhibitors have been shown to provide CV benefits in HFpEF and HFrEF patients with and without diabetes. The underlying mechanisms continue being explored. Objective: To examine the effect of hyperketonemia on myocardial blood flow (MBF) in patients with HF and T2DM. Methods: Subjects with T2DM and HF (EF &amp;lt;50%) received a 6-hr BOHB infusion or a HCO3 infusion (control). A cardiac MRI and a PET study with 18FDG and 15O water were performed before and after the infusion. Results: Twelve Subjects were studied (Age=60; BMI=32 kg/m2; A1c = 7.7%). Plasma ketone levels reached 1.6±0.2mmol/L. MBF significantly increased in six subjects (“responders” 1.05±0.13 to 1.38±0.17, p = 0.003) and decrease in six subjects (“non-responders” 1.44±0.07 to 0.95±0.08, p = 0.007). With multivariable analysis, only baseline EF was shown to significantly correlate with the increase in MBF. Conclusion: These findings suggest that patients with a higher baseline EF might be more responsive to ketones and be able to increase MBF as an additional mechanism of CV improvement. These novel results shed new light on the potential effect of ketones in different populations of patients with HF and needs to be further explored. Disclosure C. Solis-Herrera: None. Y. Qin: None. H. Honka: None. F. M. Acosta: None. A. Moody: None. A. Chavez: None. C. L. Triplitt: Speaker's Bureau; Novo Nordisk. G. D. Clarke: None. E. Cersosimo: None. R. A. DeFronzo: Speaker's Bureau; AstraZeneca. Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk. Research Support; AstraZeneca, Boehringer-Ingelheim, Merck &amp; Co., Inc. Funding Max and Minnie Tomerlin Voelcker Fund; Merck &amp; Co., Inc.

Histopathologic Validation of Stress T1 Mapping in Myocardial Ischemia: Another Step toward Clinical Translation?

Histopathologic Validation of Stress T1 Mapping in Myocardial Ischemia: Another Step toward Clinical Translation?

Abstract 484: Antidiabetic Agent, Canagliflozin, Is A Potent Vasodilator Of The Coronary Microvasculature

Objective: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are cardioprotective even in the absence of preexisting diabetic microvascular disease. Our group has shown SGLT-2 inhibitor, canagliflozin, increases myocardial perfusion without an attendant increase in angiogenesis. We hypothesize canagliflozin accentuates vasodilation of coronary microvasculature to increase perfusion. Methods: Coronary resistance arterioles (174 ± 60μm in diameter) isolated from Sprague-Dawley rats either receiving daily canagliflozin (15mg/kg, oral gavage) for four weeks (n = 4) or no treatment (n = 4) were studied in vitro in a pressurized (40mmHg), no-flow state using video microscopy. Following preconstriction of microvessels with thromboxane analog U46619 or endothelin-1, concentration response curves to vasodilatory adenosine 5’-diphosphate (ADP), acetylcholine (ACh), and sodium nitroprusside (SNP) were completed. Additionally, nitric-oxide-dependent ADP-induced vasodilation of microvessels isolated from treated rats was measured in the presence of N ω -Nitro-L-arginine methyl ester (L-NAME) 10μM. Results: Canagliflozin treatment was associated with a significant increase in endothelium-dependent vasodilatory response to ADP (p = 0.039) (Figure 1). Pretreatment with L-NAME, an inhibitor of nitric oxide synthase, eliminated this vasodilatory response. Compared to ADP, vasodilatory response to ACh was muted (p = 0.552). Endothelium-independent vasodilatory response to SNP, a nitric oxide donor, strongly trended toward an increase in the treated group (p = 0.099). Conclusions: Canagliflozin improves microvascular vasodilation in an endothelium-dependent and endothelium-independent fashion not yet described. These findings implicate both vascular endothelium and arteriolar smooth muscle cells in altered vasomotor physiology and may, in part, account for the observed increase in myocardial blood flow with canagliflozin treatment.

Dynamic myocardial perfusion computed tomography with mental stress test to detect changes in myocardial microcirculation in patients with anxiety and no obstructive coronary artery disease.

Mental stress can induce myocardial ischemia in patients with anxiety and other psychological disorders. Computed tomography myocardial perfusion imaging (CT-MPI) has the potential to quantitatively diagnose myocardial ischemia. The aim of this study was to measure changes in myocardial microcirculation perfusion (MMP) in patients with anxiety who have angina symptoms/ischemia but no obstructive coronary artery disease (INOCA) using dynamic CT-MPI in combination with a mental stress test. Patients with INOCA were divided into five subgroups (none, minimal, mild, moderate, and severe) according to the generalized anxiety disorder scale. Patients underwent dynamic CT-MPI with mental stress testing using a series of the standardized color word/arithmetic stressors. Myocardial blood flow (MBF) during resting and stress phases of CT-MPI was recorded. Fifty-eight patients with 986 segments were included for final analysis. Compared to patients with none, minimal, mild, and moderate anxiety, those with severe anxiety had the largest rate of MBF decrease and the largest MBF decrease value. At the same time, those with no anxiety had the largest rate of MBF increase, the largest MBF increase value (all p< 0.05). As anxiety intensified, the rate of MBF increased and the MBF value increased (r= -0.24, r= -0.27, p< 0.05). Concomitantly, the rate of MBF decreased and the MBF value decreased (r= 0.63, r= 0.43, p< 0.05). Dynamic CT-MPI with a mental stress test can be used to evaluate MMP in patients with anxiety and INOCA. Mental stress resulted in significant differences in changes in the rate and value of MBF among patients with different anxiety degrees. • Dynamic CT-MPI with mental stress test worked well to quantitatively evaluate myocardial microcirculation perfusion in patients with anxiety and INOCA. • The rates of MBF decrease and MBF decrease value were positively correlated with anxiety degree of anxiety patients with INOCA. • MBF change derived from CT-MPI with mental stress test had a good performance to predicting anxiety degree of patients with anxiety and INOCA.

The independent association of myocardial extracellular volume and myocardial blood flow with cardiac diastolic function in patients with type 2 diabetes: a prospective cross-sectional cohort study

BackgroundDiffuse myocardial fibrosis and microvascular dysfunction are suggested to underlie cardiac dysfunction in patients with type 2 diabetes, but studies investigating their relative impact are lacking. We aimed to study imaging biomarkers of these and hypothesized that fibrosis and microvascular dysfunction would affect different phases of left ventricular (LV) diastole.MethodsIn this cross-sectional study myocardial blood flow (MBF) at rest and adenosine-stress and perfusion reserve (MPR), as well as extracellular volume fraction (ECV), were determined with cardiovascular magnetic resonance (CMR) imaging in 205 patients with type 2 diabetes and 25 controls. Diastolic parameters included echocardiography-determined lateral e’ and average E/e’, and CMR-determined (rest and chronotropic-stress) LV early peak filling rate (ePFR), LV peak diastolic strain rate (PDSR), and left atrial (LA) volume changes.ResultsIn multivariable analysis adjusted for possible confounders including each other (ECV for blood flow and vice versa), a 10% increase of ECV was independently associated with ePFR/EDV (rest: β = − 4.0%, stress: β = − 7.9%), LAmax /BSA (rest: β = 4.8%, stress: β = 5.8%), and circumferential (β = − 4.1%) and radial PDSR (β = 0.07%/sec). A 10% stress MBF increase was associated with lateral e′ (β = 1.4%) and average E/e’ (β = − 1.4%) and a 10% MPR increase to lateral e′ (β = 2.7%), and average E/e’ (β = − 2.8%). For all the above, p < 0.05. No associations were found with longitudinal PDSR or left atrial total emptying fraction.ConclusionIn patients with type 2 diabetes, imaging biomarkers of microvascular dysfunction and diffuse fibrosis impacts diastolic dysfunction independently of each other. Microvascular dysfunction primarily affects early left ventricular relaxation. Diffuse fibrosis primarily affects diastasis.Trial registrationhttps://www.clinicaltrials.gov. Unique identifier: NCT02684331. Date of registration: February 18, 2016.

Sex- and age-specific normal values for automated quantitative pixel-wise myocardial perfusion cardiovascular magnetic resonance.

Recently developed in-line automated cardiovascular magnetic resonance (CMR) myocardial perfusion mapping has been shown to be reproducible and comparable with positron emission tomography (PET), and can be easily integrated into clinical workflows. Bringing quantitative myocardial perfusion CMR into routine clinical care requires knowledge of sex- and age-specific normal values in order to define thresholds for disease detection. This study aimed to establish sex- and age-specific normal values for stress and rest CMR myocardial blood flow (MBF) in healthy volunteers. A total of 151 healthy volunteers recruited from two centres underwent adenosine stress and rest myocardial perfusion CMR. In-line automatic reconstruction and post processing of perfusion data were implemented within the Gadgetron software framework, creating pixel-wise perfusion maps. Rest and stress MBF were measured, deriving myocardial perfusion reserve (MPR) and were subdivided by sex and age. Mean MBF in all subjects was 0.62 ± 0.13 mL/g/min at rest and 2.24 ± 0.53 mL/g/min during stress. Mean MPR was 3.74 ± 1.00. Compared with males, females had higher rest (0.69 ± 0.13 vs. 0.58 ± 0.12 mL/g/min, P < 0.01) and stress MBF (2.41 ± 0.47 vs. 2.13 ± 0.54 mL/g/min, P = 0.001). Stress MBF and MPR showed significant negative correlations with increasing age (r = -0.43, P < 0.001 and r = -0.34, P < 0.001, respectively). Fully automated in-line CMR myocardial perfusion mapping produces similar normal values to the published CMR and PET literature. There is a significant increase in rest and stress MBF, but not MPR, in females and a reduction of stress MBF and MPR with advancing age, advocating the use of sex- and age-specific reference ranges for diagnostic use.

Abstract 14158: Impact of Gender Differences on Changes in Myocardial Perfusion Following Percutaneous Coronary Intervention of Chronic Total Coronary Occlusions

Introduction. Data on gender differences in chronic total coronary occlusion (CTO) percutaneous coronary intervention (PCI) are scarce. Prior studies have demonstrated CTO PCI to reduce ischemia, however female patients are less likely to undergo revascularization. This study sought to investigate the impact of gender on myocardial perfusion changes following CTO PCI as measured by [ 15 O]H 2 O positon-emission tomography (PET) perfusion imaging. Methods. A total of 212 patients were prospectively enrolled in a single-center CTO registry and underwent single-vessel CTO PCI, combined with [ 15 O]H 2 O PET imaging at baseline and three months follow-up. Baseline and follow-up resting myocardial blood flow (MBF), hyperemic MBF and coronary flow reserve (CFR) allocated to the CTO territory were quantitatively assessed. The presence of residual ischemia was defined as hMBF ≤2.3 mL·min -1 ·g -1 in the CTO area at follow-up. Results. This study comprised 34 (16%) females and (84%) males. Mean age in females was higher compared to males (68 ± 9 vs. 61 ± 10 years, p&lt;0.01). In women, resting MBF at baseline was more elevated than in men (1.02 ± 0.24 vs. 0.84 ± 0.21 mL·min -1 ·g -1 , p&lt;0.01). Similarly, baseline hMBF was found to be higher in females (1.81 ± 0.53 vs. 1.64 ± 0.53 mL·min -1 ·g -1 , p=0.03), and showed a higher increase after CTO PCI (Δ1.06 ± 0.71 vs. Δ0.71 ± 0.66 mL·min -1 ·g -1 , p=0.01). Improvement in CFR after CTO PCI was more evident in female patients (Δ1.17 ± 1.04 vs. Δ0.82 ± 0.89, p=0.04). At three months follow-up, the proportion of patients with residual ischemia was lower in women versus men (9 (27%) vs. 91 (51%), p=0.01). Conclusions. We found a higher increase in hyperemic MBF and CFR following CTO PCI in women compared to men, as measured by serial [ 15 O]H 2 O PET imaging. In addition, lower rates of residual ischemia were observed in women. This study suggests the potential benefit of a lower threshold for CTO PCI in female patients.

Microvascular dysfunction and absolute coronary blood flow after percutaneous coronary intervention of a chronic total occlusion

Abstract The development of a coronary chronic total occlusion (CTO) causes changes in the distal epicardial vascular bed and in the microvasculature tributary of the occluded vessel. Studies with positron emission tomography showed an increase in myocardial blood flow and coronary flow reserve (CFR) after percutaneous coronary intervention (PCI) of a CTO (1). These changes are not immediate after PCI, since they usually involve a process of weeks-months (2). The FLOW-CTO study aims to evaluate the evolution of microvascular resistance and absolute coronary blood flow (ABF) after PCI of a CTO. The study consecutively included patients in 4 national centers in Spain. In these patients, a coronary physiology study was performed, immediately after PCI and at 6 months follow-up. Fractional flow reserve (FRR), CFR and index of microcirculatory resistance (IMR) were determined. ABF and microvascular resistances were determined by continuous thermodilution during maximal hyperemia induced by serum infusion (3). Coronary microvascular dysfunction (MVD) was defined as an IMR ≥25 and/or an CFR &amp;lt;2.0, in the presence of an FFR &amp;gt;0.80. We present data from the baseline study immediately after PCI of a CTO in the first 49 patients. Most patients were male (90%), with a median age of 62 years-old [IQR 56–69]. The prevalence of hypertension, dyslipidemia and diabetes were 71, 67 and 41%, respectively. The median left ventricular ejection fraction was 55% [IQR 45–60]. Eighty-six percent of the patients had exertional angina and 14% had history of congestive heart failure. The most frequently involved vessel was the right coronary artery (55%). The most used technique was antegrade guidewire escalation (74%). The median length of the devices implanted was 59±25 mm. The mean percentage of residual stenosis was 8±4%. Despite the good angiographic result, 20% of the lesions had an FFR value ≤0.80. Of those patients with a non-significant FFR value (&amp;gt;0.80), 54% had signs of MVD. Those patients with an elevated IMR (≥25) showed a non-significant trend towards a lower ABF (143±79 vs. 192±59 mL/min; p=0.1043), with significantly higher microvascular resistance (694±206 vs. 471±166 mmHg/(l/min); p=0.0328). Those patients with a reduced CFR (&amp;lt;2.0) had lower ABF (166±57 vs. 207±64 ml/min; p=0.0460) and a non-significant trend towards a higher microvascular resistance (535±240 vs. 466±195 mmHg/(l/min); p=0.3419). Diabetes mellitus was identified as a predictor of an elevated IMR (OR 6.3, 95% CI 1.1–13; p=0.046) or reduced CFR (OR 5.7, 95% CI 1.4–22, p=0.013). In our study, more than half of the patients presented signs of MVD immediately after PCI of a CTO. Despite an optimal angiographic result, in a fifth of the cases we found a significant alteration of the parameters that evaluate the epicardial circulation. Diabetes mellitus was found as a predictor of MVD after PCI of a CTO. Funding Acknowledgement Type of funding sources: None.

Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report

ObjectiveCardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and < 80%), with or without previous percutaneous coronary intervention (> 6 months) but no HF.MethodsThis was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by 13N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT 03313752).Results16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 μmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 μmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; pint = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; pint = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054).ConclusionsSGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction.Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752

Effects of passive heat exposure on myocardial blood flow in healthy young and older adults

INTRODUCTIONExtreme heat is associated with a greater risk of cardiovascular mortality in older adults (≥60 years). However, the pathophysiology that links extreme heat and cardiovascular mortality remains unknown. One possibility is that myocardial oxygen requirements during heat exposure cannot be met by sufficient increased in myocardial blood flow (MBF) thereby predisposing to ischemia. However, the extent to which MBF increases during heat exposure, and whether age alters this increase, is unknown. The objective of this study was to test the hypothesis that passive heat exposure increases MBF and that this increase is attenuated in healthy older adults.METHODSMBF was measured during passive heat exposure (water‐perfused suit) in 15 young (27 years, range: 24‐30) and 14 older (68 years, range: 64‐72) healthy adults with 82‐Rubidium positron emission tomography. Four MBF measurements were performed: prior to heat exposure (baseline) and at an increase in rectal temperature of 0.5°C, 1.0°C, and 1.5°C. Heart rate (ECG) and blood pressure (automated auscultation) were also measured to calculate rate pressure product (RPP; heart rate x systolic blood pressure). MBF reserve (MFR) was calculated by dividing the MBF at 1.5°C by baseline MBF.RESULTSBaseline MBF was 0.76 ± 0.19 mL/min/g in young adults and 0.88 ± 0.21 mL/min/g in older adults (p=0.14). MBF increased similarly in both groups during heat exposure (interaction, p=0.31). Nonetheless, older adults displayed a lower MFR at an increase in rectal temperature of 1.5°C (young: 2.3 ± 0.7 vs. older: 1.8 ± 0.4, p=0.03). The lower MFR in older adults was paralleled by an attenuated increase in RPP during passive heating (at + 1.5°C, young: 6.8 ± 1.7vs. older: 3.6 ± 2.2 bpm·mmHg·103, p&lt;0.01), due to a blunted increase in heart rate (young: 50 ± 12vs. older: 34 ± 14 bpm, p&lt;0.01). When the change in MBF was plotted against the change in RPP, the slope of the regression lines did not differ between young (0.11 [95% CI; 0.07, 0.15]) and older (0.08 [95% CI; 0.04, 0.11] mL/g/min/ bpm·mmHg·103,p=0.24) adults.CONCLUSIONThese results show that passive heat exposure roughly doubles MBF in healthy young and older adults. Furthermore, the results demonstrate that the increase in MBF during passive heat exposure is not altered by age and is proportional to the increase in RPP.

Prognostic Significance of Myocardial Blood Flow Quantification for Major Adverse Cardiac Events: A Systematic Review and Meta-analysis.

Chronic coronary syndromes involve reduced myocardial blood flow (MBF). MBF is a reliable predictor of outcomes, independent of the presence of significant stenosis. Whether MBF can predict major adverse cardiac events (MACE) during long-term follow-up is unknown. PubMed, Embase, Cochrane, CNKI, and WANFANG were searched for papers published up to January 2021. The exposure was the incremental unit of stress MBF (mL/g/min) or low MBF versus high MBF. The imaging examinations included positron emission tomography/computed tomography and coronary magnetic resonance. The study outcome was the occurrence of MACE during follow-up, summarized as time-to-event hazard ratios (HRs) and 95% confidence intervals (CIs). Six studies (300 MACEs in 2326 patients) were included. Four studies presented stress MBF data by unit increments. The pooled HR showed that an increase in stress MBF by 1 mL/g/min is a protective factor for MACE (HR = 0.32; 95% CI, 0.18-0.57; I2 = 62.9%, Pheterogeneity = 0.044). Two studies reported stress MBF as low/high. The results showed that a high-stress MBF was protective against MACEs (HR = 0.43; 95% CI, 0.24-0.78; I2 = 39.5%, Pheterogeneity = 0.199). Quantification of stress MBF using positron emission tomography/computed tomography and coronary magnetic resonance might have incremental predictive value for future MACEs in a population at intermediate to high cardiovascular risk. The results will require validation in large prospective randomized controlled trials.

Use of quantitative myocardial perfusion mapping by CMR for characterisation of ischaemia in patients post coronary artery bypass graft surgery

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background Quantitative myocardial perfusion mapping using Cardiac Magnetic Resonance (CMR) imaging is used for evaluation of ischaemia in the context of native vessel coronary disease, but its diagnostic performance in patients with grafts is not well established. Perfusion defects are often detected in these patients, but whether these are a consequence of a technical limitation (delayed contrast arrival from graft conduits) or a true reflection of reduced myocardial blood flow is unclear. Methods 39 patients undergoing stress perfusion CMR with previous coronary artery bypass graft (CABG) surgery, unobstructed left internal mammary artery (LIMA) grafts to the left anterior descending (LAD) artery on coronary angiography and no CMR evidence of prior LAD infarction were included. Myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) were evaluated with quantitative perfusion mapping and the factors determining MBF in the LIMA-LAD territory (AHA segments 1,2,7,8,13,14), including the impact of delayed contrast arrival through the LIMA graft were evaluated. Results In 28 out of 39 cases a myocardial perfusion defect was reported on visual assessment in LIMA-LAD myocardial territory, despite the presence of unobstructed LIMA graft and no LAD infarction. Chronic total occlusion (CTO) of the native LAD was an independent predictor of stress MBF (B=-0.36, p =0.027) and the strongest predictor of MPR (B=-0.55, p 0.005) within the LIMA-LAD myocardial territory after adjusting for age, left ventricular (LV) ejection fraction, and presence of diabetes. CTO of the native LAD was associated with a reduction in stress MBF in the basal myocardial segments (-0.57ml/g/min, p = 0.002) but had no effect on the MBF of apical segments (-0.31ml/g/min, p = 0.084). Increasing the maximum value for allowable arterial delay (TA) of contrast in the quantitative mapping algorithm resulted in a small increase in myocardial blood flow in the LIMA-LAD territory both at stress (0.07 ± 0.08ml/g/min, p &amp;lt; 0.001) and rest (0.06 ± 0.05ml/g/min, p &amp;lt; 0.001). Conclusions Perfusion defects detected in LIMA-LAD subtended territories are common despite graft patency. These defects are likely to represent genuine reduction in MBF, resulting from native LAD coronary occlusion. Prolonged contrast transit time associated with LIMA grafts results in small underestimation of MBF as measured by quantitative CMR perfusion mapping, but does not account for the degree of MBF reduction seen in these patients. Figure 1. Study patient with unobstructed LIMA to LAD graft and evidence of inducible perfusion defect in LIMA-LAD territories. (A): First pass perfusion CMR imaging. (B): Perfusion mapping showing reduced stress MBF in mid antero-septum (0.85ml/g/min) compared to the apical septum (1.65ml/g/min). (C): Late gadolinium enhancement showing no evidence of previous infarction. (D,E): Coronary angiography demonstrating unobstructed LIMA graft (D) and anastomosis site (E). Abstract Figure 1.

Splenic switch-off as a predictor for coronary adenosine response: validation against 13N-ammonia during co-injection myocardial perfusion imaging on a hybrid PET/CMR\xa0scanner

BackgroundInadequate coronary adenosine response is a potential cause for false negative ischemia testing. Recently, the splenic switch-off (SSO) sign has been identified as a promising tool to ascertain the efficacy of adenosine during vasodilator stress cardiovascular magnetic resonance imaging (CMR). We assessed the value of SSO to predict adenosine response, defined as an increase in myocardial blood flow (MBF) during quantitative stress myocardial perfusion 13 N-ammonia positron emission tomography (PET).MethodsWe prospectively enrolled 64 patients who underwent simultaneous CMR and PET myocardial perfusion imaging on a hybrid PET/CMR scanner with co-injection of gadolinium based contrast agent (GBCA) and 13N-ammonia during rest and adenosine-induced stress. A myocardial flow reserve (MFR) of > 1.5 or ischemia as assessed by PET were defined as markers for adequate coronary adenosine response. The presence or absence of SSO was visually assessed. The stress-to-rest intensity ratio (SIR) was calculated as the ratio of stress over rest peak signal intensity for splenic tissue. Additionally, the spleen-to-myocardium ratio, defined as the relative change of spleen to myocardial signal, was calculated for stress (SMRstress) and rest.ResultsSixty-one (95%) patients were coronary adenosine responders, but SSO was absent in 18 (28%) patients. SIR and SMRstress were significantly lower in patients with SSO (SIR: 0.56 ± 0.13 vs. 0.93 ± 0.23; p < 0.001 and SMRstress: 1.09 ± 0.47 vs. 1.68 ± 0.62; p < 0.001). Mean hyperemic and rest MBF were 2.12 ± 0.68 ml/min/g and 0.78 ± 0.26 ml/min/g, respectively. MFR was significantly higher in patients with vs. patients without presence of SSO (3.07 ± 1.03 vs. 2.48 ± 0.96; p = 0.038), but there was only a weak inverse correlation between SMRstress and MFR (R = -0.378; p = 0.02) as well as between SIR and MFR (R = -0.356; p = 0.004).ConclusionsThe presence of SSO implies adequate coronary adenosine-induced MBF response. Its absence, however, is not a reliable indicator for failed adenosine-induced coronary vasodilatation.

Quantitative cardiovascular magnetic resonance myocardial perfusion mapping to assess hyperaemic response to adenosine stress.

Assessment of hyperaemia during adenosine stress cardiovascular magnetic resonance (CMR) remains a clinical challenge with lack of a gold-standard non-invasive clinical marker to confirm hyperaemic response. This study aimed to validate maximum stress myocardial blood flow (SMBF) measured using quantitative perfusion mapping for assessment of hyperaemic response and compare this to current clinical markers of adenosine stress. Two hundred and eighteen subjects underwent adenosine stress CMR. A derivation cohort (22 volunteers) was used to identify a SMBF threshold value for hyperaemia. This was tested in a validation cohort (37 patients with suspected coronary artery disease) who underwent invasive coronary physiology assessment on the same day as CMR. A clinical cohort (159 patients) was used to compare SMBF to other physiological markers of hyperaemia [splenic switch-off (SSO), heart rate response (HRR), and blood pressure (BP) fall]. A minimum SMBF threshold of 1.43 mL/g/min was derived from volunteer scans. All patients in the coronary physiology cohort demonstrated regional maximum SMBF (SMBFmax) >1.43 mL/g/min and invasive evidence of hyperaemia. Of the clinical cohort, 93% had hyperaemia defined by perfusion mapping compared to 71% using SSO and 81% using HRR. There was no difference in SMBFmax in those with or without SSO (2.58 ± 0.89 vs. 2.54 ± 1.04 mL/g/min, P = 0.84) but those with HRR had significantly higher SMBFmax (2.66 1.86 mL/g/min, P < 0.001). HRR >15 bpm was superior to SSO in predicting adequate increase in SMBF (AUC 0.87 vs. 0.62, P < 0.001). Adenosine-induced increase in myocardial blood flow is accurate for confirmation of hyperaemia during stress CMR studies and is superior to traditional, clinically used markers of adequate stress such as SSO and BP response.

Efficacy of Trimetazidine and Sulodexide in Patients with Microvascular Angina

Background . Despite the progress in the diagnostics of microvascular angina ( МА ) there is no effective pathogenetic therapy. Aim . To study the effect of trimetazidine and sulodexide as a part of drug therapy on clinical manifestations, exercise tolerance, quality of life, myocardial perfusion and endothelial function in patients with MA. Material and methods . Patients with MA (n=90) were included into the study and randomized into 3 groups. Patients of the first group (control; n=30) received standard antianginal therapy. The second group (treatment group; n=30) received standard therapy and sulodexide (1 ampoule of 600 IU intramuscularly for 10 days, then 1 capsule of 250 IU, 2 times a day). Patients of the third group (treatment group; n=30) received standard therapy and trimetazidine with modified release 35 mg 2 times a day. Evaluation of angina symptoms and quality of life by the Seattle Questionnaire, stress (treadmill) test, positron emission tomography (baseline, adenosine test, cold-pressor test), peripheral arterial tonometry were performed at baseline and 3 months after starting treatment. Results . After 3 months of treatment a significant improvement in symptoms, quality of life and results of stress-test were observed only among patients of treatment groups, most pronounced in the 3rd group. Patients of this group showed an increase in myocardial blood flow &gt;25% according to positron emission tomography (from 86.2±29.7 to 129.5±41.0 ml/100g/min, p&lt;0.05 for anterior interventricular artery; from 93.3±30.5 to 131.7±32.7 ml/100g/min, p&lt;0.05 for circumflex artery; from 91.3±30.4 to 135.9±41.1 ml/100g/min, p&lt;0.05 for right coronary artery) and a significant increase in coronary reserve, as well as an improvement in endothelial function: an increase in coronary reserve of endothelium-dependent vasodilation, an increase in the reactive hyperemia index according to peripheral arterial tonometry (from 1.44±0.14 to 1.73±0.18, p&lt;0.001). Conclusion . Improvement of the clinical picture, quality of life, myocardial perfusion, and endothelial function was observed among microvascular angina patients who were treated with standard antianginal therapy and trimetazidine.

Позитронная эмиссионная томография с рубидием-82 в исследованиях перфузии миокарда

This review considers literature sources on myocardial perfusion studies using positron emission tomography with rubidium-82. The history of the development of the method, the protocols of the study, the dissymmetric data are analyzed, and comparisons are made with other positron emitters that are used in clinical practice and research to study myocardial blood supply. The use of PET/CT with rubidium-82 makes it possible to obtain valuable diagnostic information and it allows to measure myocardial blood directly and make a separate assessment of the coronary arteries function. Due to the fact that the production of rubidium-82 does not require an on-site cyclotron and a radiochemical laboratory, this method of imaging is more accessible than other positron emitters used for the same purpose. Also, the study is not associated with significant discomfort for the patient, since the full stress/rest imaging protocol requires less than half an hour. However, the use of rubidium-82 has a number of drawbacks, including the relatively low sharpness of the resulting image due to the high energy of the emitting positrons. Also there is a necessity for a mathematical correction of the roll-off phenomenon, which is a decrease in radiopharmaceutical extraction with an increase in myocardial blood flow. Due to the short half-life period, the provision of stress tests with ergometers is difficult. It needed to use pharmacological stress tests. In addition, usage of rubidium-82 is characterized by a high cost both due to the expensive production of the parent isotope, strontium-82, and the need for frequent replacement of generators – on average, 11 to 13 times a year.