Prediabetes and Non Obstructive Coronary Atherosclerosis.
Condition: PreDiabetes
MeSH terms: Prediabetic State; Glucose Intolerance
Study type: Observational

Summary: 
      Objectives: Prediabetes may condition an early endothelium dysfunction, and the development
      of non obstructive coronary stenosis (NOCS). Indeed, authors' study aim was to investigate
      the endothelial dysfunction, and Major Adverse Cardiac Events (MACE) in prediabetics vs.
      normo glycemic subjects.

      Materials and Methods: 308 patients with evidence of left anterior descending (LAD) coronary
      NOCS (<50% luminal stenosis), will entere prospectively into a database. After assessment of
      endothelial coronary dysfunction by acetilcoline infusion, 86 propensity score matched (PSM)
      prediabetics and 86 PSM normoglycemics will be consecutive enrolled in the study.
    

Detailed description: 
      INTRODUCTION Prediabetes is a heterogeneous pathological condition diagnosed by the evidence
      of fasting plasma glucose of ≥5.6 mmol/L but <7.0 mmol/L (100-125 mg/dL; impaired fasting
      glucose [IFG]), a 2-hour glucose of ≥7.8 mmol/L but <11.1 mmol/L during a 75 g oral glucose
      tolerance test (GTT) (140-199 mg/dL; impaired glucose tolerance [IGT]), or a plasma
      hemoglobin (Hb) A1c of ≥5.7% but <6.5%. Epidemiological data confirm prediabetes as an
      increasing disease with a prevalence in the adults population of United States >38%. However,
      prediabetics present an increased risk to develop diabetes, and cardiovascular disease, then
      associated to worse prognosis. The common pathogenic mechanism linking prediabetes to
      cardiovascular disease is represented by the early insurgence of coronary artery dysfunction.
      It looks intuitive to speculate that, in prediabetics the hyperglycemia may early condition
      the coronary artery dysfunction, by a hyper activation of inflammatory and oxidative
      processes at level of endothelium covering the intima surface of coronary vessels. To date,
      the coronary artery dysfunction in prediabetics is well characterized by the endothelium
      dysfunction hyperglycemia induced. In fact, the endothelial dysfunction in prediabetics is
      characterized by a loss of vasodilation in response to sheer stress induced by release of an
      occlusive cuff (flow-mediated dilation) or pharmacological stimuli causing nitric oxide (NO)
      synthase activation such as acetylcholine. Moreover, in prediabetics the hyperglycemia may
      induce endothelial dysfunction evident in the early pathogenesis of atherosclerosis, such as
      it may be for patients with non obstructive coronary stenosis (NOCS). However, this early
      insurgence of coronary artery dysfunction in prediabetics may secondary lead to worse
      prognosis by an increasing number of Major Adverse Cardiac Events (MACE). On the other hand,
      actually a great discordance in literature exists about the correlation between NOCS in
      prediabetics and the associated clinical outcomes. In fact, authors recently reported that,
      asymptomatic prediabetics enrolled for early detection of coronary artery disease, and
      assessed by coronary computed tomography angiography, were not associated with an increased
      risk of subclinical coronary atherosclerosis. On the contrary, because the hyperglycemia may
      induce in prediabetics a higher expression of inflammatory and oxidative pathways, these
      multiple altered molecular pathways may consequently condition an endothelial dysfunction.
      However, limited data are actually evident about the impact of the glycemic status on the
      risk of subclinical coronary atherosclerosis in NOCS prediabetics as compared to
      normoglycemics patients. Therefore, author study hypothesis will be as first that, NOCS
      prediabetics vs. normoglycemics may present a higher level of inflammatory and oxidative
      markers. As second, these altered pathways may lead to an early endothelial dysfunction also
      in presence of monovessel NOCS. Finally, this pathogenic status may subsequently condition
      the worse prognosis in prediabetics vs. normoglycemics. Indeed, authors' study aim will be to
      investigate the endothelial dysfunction and the related MACE at 24 months of follow up in
      prediabetics vs. normo glycemic subjects with diagnosis of monovessel NOCS diagnosed by
      coronary angiography and infusion of acetylcholine.

      METHODS Authors will screen at the Department of Cardiology, Hospital Cardarelli, Naples,
      Italy, and at Department of Cardiovascular Diseases, John Paul II Research and Care
      Foundation, Campobasso, Italy, patients having stable angina pectoris, with a positive stress
      test for myocardial ischemia, and no change in the frequency, duration, or intensity of
      clinical symptoms within 4 weeks, and referred for coronary artery angiography. However,
      these patients will receive a coronary angiography, and 267 patients with evidence of left
      anterior descending (LAD) coronary NOCS (<50% luminal stenosis), and no physiologically
      significant fractional flow reserve (FFR >0.80), will enter prospectively into a database.
      After the diagnosis of monovessel LAD-NOCS, authors will evaluate in these patients the
      endothelial coronary vascular function at baseline and after each infusion of acetylcholine.
      However these patients will be divided in subjects with normal endothelial function vs.
      subjects with endothelial dysfunction. Patients with no coronary disease detected by coronary
      angiography, presence of both obstructive and non-obstructive stenosis, left ventricular
      ejection fraction <50%, previous myocardial infarction, previous percutaneous coronary
      intervention and/or coronary bypass grafting, Tako-tsubo cardiomyopathy, myocarditis,
      impaired renal function or stroke will be excluded. To date 86 propensity score matched (PSM)
      prediabetics and 86 PSM normoglycemics will be consecutive enrolled in the study. Prediabetes
      will be defined by IFG, and IGT with an HbA1c value in the range of 6.4% (1). The analyses of
      all angiographic data will be performed by the interventional cardiologists, blinded to
      patient categorization, who will review selected cases with NOCS. After an overnight fast,
      plasma glucose and glycated haemoglobin (HbA1c) levels will be measured using enzymatic
      assays. At the Department of Medical, Surgical, Neurological, Aging and Metabolic Sciences,
      University of Campania "Luigi Vanvitelli", Italy, authors will practice for all patients
      quarterly clinical evaluation, routine analyses, plasma glucose and glycated haemoglobin
      (HbA1c) levels measurements, and cardiovascular evaluation as outpatients for 24 months after
      the coronarography. The study endpoints will be the assessment of oxidative stress,
      inflammatory tone, and MACE at 24 months follow up. The study will be conducted in accordance
      with the Declaration of Helsinki. The ethics committees of all participating institutions
      will approve the protocol. All patients will be informed about the study nature, and will
      give their written informed and signed consent to participate in the study.

      Coronary angiography and endothelial function assessment. Experienced physician will perform
      routine diagnostic coronary angiography (General Electric, Discovery IGS 740) by using
      standard clinical protocols. Coronary angiography will be performed to discriminate and
      select patients with monovessel LAD and NOCS, as a stenosis <50% of vessel lumen, and with a
      fractionated flow reserve (FFr) >0.80 (8, 9). After the diagnosis of monovessel LAD-NOCS, in
      these patients authors will evaluate the endothelial coronary vascular function at baseline
      and after each infusion of acetylcholine. However, coronary artery diameter will be measured
      at baseline and after the infusion of acetylcholine by an independent investigator blinded to
      Doppler velocity data, and using a previously described computer-based image analysis system.
      The infusion protocol of acetylcholine will be terminated when the highest molar
      concentration of acetylcholine (1,024 mol/l) will be reached (8). Endothelial-dependent
      coronary blood flow (CBF) will be then calculated by the formula: CBF ¼ p(average peak
      velocity)(coronary artery diameter/2)2 (8). The inter observer and intra observer
      reproducibility of the CBF calculation will be about 5%. The maximal percent increase in CBF
      in response to acetylcholine compared with the CBF at baseline will be then calculated, and
      all measurements will be performed in the segment 5 mm distal to the tip of the Doppler
      guidewire. Moreover, after each acetylcholine infusion, the coronary artery diameter will be
      measured in the same segment of the vessel. The maximal effect of acetylcholine will be
      expressed as percent change in coronary artery diameter using quantitative coronary
      angiography (QCA, Medis Corporation, Leiden, the Netherlands) (representing epicardial
      endothelial function) and percent change in the CBF (representing microvascular endothelial
      function) relative to baseline (8).

      Biochemical analyses. Venous blood samples, obtained from all participants in the study at
      baseline and during follow up phases, will be centrifuged at 3,000 rotations/min, and
      serum/plasma samples will be collected and stored at -80°C until assayed. Serum levels of
      high-sensitivity C-reactive protein (hs-CRP), Interleukine 1 (IL1) and 6 (IL 6), and TNF
      alpha will be measured as an inflammatory biomarker. In addition authors will measure the
      number of white blood cells (WBC), granulocytes, platelets, and blood values of Nitrotirosine
      as markers of oxidative stress on admission before coronary angiography and at follow up.

      Statystical analysis SPSS version 23.0 (IBM statistics) will be used for all statistical
      analyses. Categorical variables will be presented as frequencies (percentages), and
      continuous variables as mean ± standard deviation. For comparisons between prediabetics and
      normoglycemics (controls) with normal epicardial endothelial function and those with
      epicardial endothelial dysfunction, propensity score matching will be developed from the
      predicted probabilities of a multivariable logistic regression model predicting mortality and
      events according to age, sex, hypertension, dyslipidaemia, smoking history, family history,
      baseline therapies, metabolic characteristics and coronary lesions. Overall survival and
      event-free survival will bee presented using Kaplan-Meier survival curves, and compared using
      the log-rank test. Univariable Cox models will be then used to compare event risks. The
      resulting hazard ratios (HRs) and 95% confidence intervals (CIs) will be reported. Two-tailed
      P values <.05 will be taken to indicate statistical significance.
    

Intervention name(s): coronary artery angiography
Intervention type(s): Device
Intervention description(s): In all patients authors performed a coronary artery angiography for detection of coronary artery stenosis.
Observational model: Case-Control
Time perspective: Retrospective
Sampling method: Probability Sample
Study population: 
        a cohort of patients divided in prediabetics (n 86) vs. normoglycemics (n 86) that
        underwent coronary artery angiography for chest pain.