The Association Between Cardiovascular Autonomic Function and Changes in Kidney and Myocardial Function in Type 2 Diabetes and Healthy Controls

BackgroundThe mechanisms linking cardiovascular autonomic neuropathy, diabetic kidney disease and cardiovascular mortality in type 2 diabetes are widely unknown. We investigated the relationship between baseline cardiovascular autonomic function and changes in kidney and myocardial function over six years in patients with type 2 diabetes and healthy controls.MethodsPost-hoc analysis of a cohort study in 24 patients with type 2 diabetes and 18 healthy controls. Baseline determinants were cardiovascular autonomic reflex tests (heart rate response to: standing (30:15); deep breathing (E:I); and the Valsalva test) and time- and frequency-domain heart rate variability indices. Outcomes were changes in estimated glomerular filtration rate (eGFR), albuminuria, myocardial flow reserve (MFR) measured by cardiac 82Rb Positron emission tomography computed tomography (PET/CT), and coronary artery calcium score (CACS).ResultsMean age at inclusion was 61 ± 10 years and 36% were female. Mean follow up time was 6 ± 0 years. A lower response in heart rate to the Valsalva test (corresponding to weaker autonomic function) was associated with a larger decline in eGFR (p=0.04), but not significantly after adjustment for sex, baseline age, smoking status, systolic blood pressure, heart rate, HbA1c, body mass index and baseline eGFR (p=0.12). A higher baseline response in heart rate to standing (30:15) was associated with a larger decline in myocardial flow reserve in the unadjusted analysis (p=0.02) and after adjustment (p=0.02). A higher response in heart rate to the Valsalva maneuver was associated with a larger increase in CACS (p = 0.02), but the association became insignificant after adjustment (p = 0.16).ConclusionA lower response in heart rate to the Valsalva test was associated with a larger decline in kidney function, indicating that autonomic dysfunction may predict future loss of kidney function. However, we did not find any association between lower values in cardiovascular autonomic function at baseline and a worsening in albuminuria, myocardial function, or atherosclerotic burden.

Comparison of the Prognostic Value of Global and Regional Myocardial Flow Capacity Radius, Myocardial Flow Reserve, and Stress Myocardial Blood Flow Using Rubidium-82 with SiPM PET/CT

Purpose The aim of this study was to assess the most reliable quantitative variable on Rubidium-82 (82Rb) cardiac PET/CT for predicting major adverse cardiovascular events (MACE), on the latest PET camera using silicon photomultipliers digital readout (SiPM) technology. Methods We prospectively enrolled 274 consecutive participants with suspected myocardial ischemia. Participants underwent 82Rb cardiac SiPM PET/CT and were followed-up for MACE over 652 days (interquartile range: 559 to 751 days). For each participant, global and regional myocardial flow reserve (MFR), stress myocardial blood flow (stress MBF) and their combination as myocardial flow capacity radius (MFC radius) were measured. Results On receiver operator curve analysis, MACE prediction was similar for global and regional MFR, stress MBF, and MFC radius (area under the curve; (i) Global: 0.70 vs. 0.71 and 0.73, and (ii) Regional: 0.71 vs. 0.71 and 0.73, respectively, p > 0.1 for all pairwise comparisons). On multivariable analysis, (i) Global: MFR < 1.98, stress MBF < 1.94 mL/g/min, and MFC radius < 3.12, as well as (ii) Regional: MFR < 1.75, stress MBF < 1.75 mL/g/min, and MFC radius < 2.7, emerged all as similar independent predictors of MACE (p < 0.001 for all). Conclusions Using the latest SiPM PET technology with 82Rb, global and regional MFR, stress MBF, and MFC radius are similar powerful predictors of cardiovascular event.

Capabilities of Modern Semiconductor Gamma Cameras in Radionuclide Diagnosis of Coronary Artery Disease

This paper presents a review of the literature concerning the clinical application of modern semiconductor (CZT) gamma cameras in the radioinuclide diagnosis of coronary artery disease. It contains information on the diagnostic efficacy of myocardial perfusion studies performed with those cameras compared with the widely used scintillation (Anger) cameras, an overview of their effectiveness in comparison with coronary angiography (also fractional flow reserve) and currently available clinical results of a myocardial flow reserve measured with a dynamic SPECT study. Introduction of this imaging modality to the measurement of a myocardial flow reserve aims to facilitate access to this type of study compared to the less available and more expensive PET method used so far.

Inter- and Intraobserver Repeatability of Myocardial Flow Reserve Values Determined with SPECT Study Using a Discovery NM530c Camera and Corridor 4DM Software

Background: Myocardial blood flow (MBF) and flow reserve (MFR) examination, especially useful in the diagnosis of multivessel coronary artery disease (CAD), can be assessed with a cadmium-zinc-telluride (CZT) SPECT gamma camera, as an alternative to the expensive and less available PET. However, study processing is not free from subjective factors. Therefore, this paper aims to evaluate intra- and interobserver repeatability of MBF and MFR values obtained by the same operator and two independent operators. Methods: This study included 57 adult patients. MBF and MFR were assessed using a Discovery NM530c camera in a two-day, rest/dipyridamople protocol, using 99mTc-MIBI. Data were processed using Corridor4DM software, twice by one operator and once by another operator. Results: The repeatability of the assessed values was quite good in the whole myocardium, LAD and LCX vascular territories, but was poor in the RCA territory. Conclusions: The poor repeatability of MBF and MFR in RCA vascular territory can be explained by poor automatic orientation of the heart axis during post-processing and a so-called “cardiac creep” phenomenon. Better automatic heart orientation and introduction of automatic motion correction is likely to drastically improve this repeatability. In the present state of the software, PET is better for patients requiring assessment of MFR in the RCA territory.

Comorbidities associated with reduced myocardial flow reserve in non-obstructive disease

Introduction Microvascular Dysfunction defined as a Myocardial Flow Reserve (MFR) &lt;2 or &lt;2.5 depending on the center, may present in the absence of significant obstruction (1,2); it is included as a diagnosis criteria of Microvascular Angina (MVA) (3,4) and is an independent risk factor associated with poor prognosis (5–7). Traditional Coronary Artery Disease (CAD)risk factors have also been associated with MVA (8–10), however, there is reduced data in latin populations with high prevalence of comorbidities. The aim of this study was to identify the comorbidities that alter MFR with 13N-ammonia Positron Emission Tomography/Cardiac Tomography (PET/CT) and Cardiac Computed Tomography Angiography (CCTA) in a cardiovascular imaging referral center. Methods Retrospective cross-sectional study of patients with suspected CAD in which both PET/CT and CCTA were performed. Inclusion:CCTA with obstruction &lt;50%. Exclusion: incomplete study, previous infarction or intervention. Clinical data was assessed. Mean (±DE) or median (interquartile range) to present continuous variables according to their distribution; T student or U Man Whitney to compare them. For each variable two groups were conformed depending on its presence or absence in order to compare MFR between them. Statistical analysis was performed with Statistical Package for Social Science (SPSs Inc, Chicago, IL; version 23.0) and GraphPad Prism version 9.0. p&lt;0.05 was considered as significant. Results 335 patients included. MFR difference for each variable: female sex, hypertension (HT), Type 2 diabetes (T2D) and smoking – Appendix 1. Significant MFR difference for HT (p=0.024) and T2D (p=0.046). Severe ischemia had significant MFR reduction (p=0.006); patients with both HT and mild ischemia (p=0.018) – Appendix 2. Discussion Individuals with HT and T2D had a significantly lower MFR, consistent with previous studies (8,9). Absence of correlation with other risk factors, such as smoking (10) and female sex (11); latter may be caused by a significant lower number of women (108 vs 227). Further analysis in this subgroup ought to be done. When comparing MFR between level-of-ischemia groups, microvascular function was not reduced until severe ischemia. Remarkably, if we analyze the coexistence of HT with ischemia, MFR is reduced even in patients with mild ischemia. This finding highlights the importance of HT which alters function in early stages even in the absence of significant obstruction. This is one of the first studies correlating MFR with comorbidities in our population. Limitations the retrospective nature of the study. Conclusions MFR non-invasive assessment by PET/CT allows identifying very early stages of MVD, even in asymptomatic patients and when there's no evidence of ischemia or CAD. Therefore, timely recognition of this problem is mandatory to implement action strategies to stop the triggered events' cascade. FUNDunding Acknowledgement Type of funding sources: None.

Coronary flow quantification estimated by dynamic 320-detector CT angiography: validation by 13N ammonia PET myocardial flow reserve

Objectives: Resting coronary flow index (rCFI) estimated by 320-detector low-dose dynamic coronary CT angiography (CCTA) is a direct flow quantification using intracoronary attenuation. We propose modified-rCFI from new protocol combining dynamic scan and standard CCTA using dose-modulation, and validate its consistency with quantitative values and ischemia depicted by 13N-ammonia PET (NH3-PET). Methods: 46 patients who underwent dynamic CCTA and NH3-PET for coronary artery disease were evaluated using original rCFI in 21 patients and modified-rCFI in 25 patients. Two types of rCFI were calculated for three major coronary arteries. Myocardial blood flow (MBF) at rest and stress, myocardial flow reserve (MFR), and the presence or absence of ischemia for three major territories were depicted by NH3-PET. Coronary territories were categorized as territories with MFR <2.0, ≥2.0, or with and without ischemia. Receiver operating characteristic analysis was performed to determine the optimal cut-off of rCFI to distinguish territories with MFR <2.0 or the presence of ischemia. Results: rCFI and modified-rCFI had significant positive correlations with stress MBF and MFR. The optical cut-offs of rCFI and modified-rCFI of 0.39 and 0.61 could detect territories with MFR <2.0, with AUCs of 0.75 and 0.73, sensitivities of 48 and 34%, and specificities of 97 and 98%. Optimal cut-offs of rCFI and modified-rCFI distinguished ischemic segments from non-ischemic segments, with AUCs of 0.75 and 0.91, sensitivities of 53 and 50%, and specificities of 93 and 95%. Conclusion: Two types of rCFI correlated with quantitative values from NH3-PET, and were consistent with a high specificity in detecting functional ischemia. Advances in knowledge: rCFI can contribute as additional functional test over standard CCTA in clinical work-up.

Association Between Impaired Myocardial Flow Reserve on 82 Rubidium Positron Emission Tomography Imaging and Adverse Events in Patients With Autoimmune Rheumatic Disease

Background: Coronary microvascular dysfunction has been described in patients with autoimmune rheumatic disease (ARD). However, it is unknown whether positron emission tomography (PET)-derived myocardial flow reserve (MFR) can predict adverse events in this population. Methods: Patients with ARD without coronary artery disease who underwent dynamic rest-stress 82 Rubidium PET were retrospectively studied and compared with patients without ARD matched for age, sex, and comorbidities. The association between MFR and a composite end point of mortality or myocardial infarction or heart failure admission was evaluated with time to event and Cox-regression analyses. Results: In 101 patients with ARD (88% female, age: 62±10 years), when compared with matched patients without ARD (n=101), global MFR was significantly reduced (median: 1.68 [interquartile range: 1.34–2.05] versus 1.86 [interquartile range: 1.58–2.28]) and reduced MFR (<1.5) was more frequent (40% versus 22%). MFR did not differ among subtypes of ARDs. In survival analysis, patients with ARD and low MFR (MFR<1.5) had decreased event-free survival for the combined end point, when compared with patients with and without ARD and normal MFR (MFR>1.5) and when compared with patients without ARD and low MFR, after adjustment for the nonlaboratory-based Framingham risk score, rest left ventricular ejection fraction, severe coronary calcification, and the presence of medium/large perfusion defects. In Cox-regression analysis, ARD diagnosis and reduced MFR were both independent predictors of adverse events along with congestive heart failure diagnosis and presence of medium/large stress perfusion defects on PET. Further analysis with inclusion of an interaction term between ARD and impaired MFR revealed no significant interaction effects between ARD and impaired MFR. Conclusions: In our retrospective cohort analysis, patients with ARD had significantly reduced PET MFR compared with age-, sex-, and comorbidity-matched patients without ARD. Reduced PET MFR and ARD diagnosis were both independent predictors of adverse outcomes.