E. Cosson

Are silent coronary stenoses predictable in diabetic patients and predictive of cardiovascular events

OBJECTIVES We have previously shown that silent coronary stenoses (CS) were predictors of subsequent major cardiac events in diabetic patients with silent myocardial ischemia (SMI). The aim of this study was to determine their correlates and their prognostic value for other cardiovascular events. METHODS 362 asymptomatic diabetic patients, without prior myocardial infarction, with > or =1 additional risk factor and a normal resting electrocardiogram underwent a myocardial scintigraphy to detect SMI. The patients with SMI subsequently underwent a coronary angiography to detect CS. A total of 345 (95.3%) patients were followed up for 41 +/- 24 months with regard to the occurrence of stroke, gangrene or a peripheral revascularization procedure, exercise occurrence of angina, and nonfatal arrhythmia. RESULTS 121 patients had SMI and 44 had CS. The univariate correlates of CS were age > 65 years (Odds Ratio 2.1 [CI 95%: 1.1-4.0]; p=0.021), male gender (OR 3.1 [1.5-6.3]; p=0.001), smoking (OR 2.8 [1.4-5.6]; p=0.004), > or =2 risk factors (OR 2.1 [1.09-4.09]; p=0.024) and peripheral arterial disease (OR 3.2 [1.2-8.7]; p=0.018). Logistic regression showed that age > 65 years (p=0.034), male gender (p=0.001) and > or =2 risk factors (p=0.013) were independently associated with the presence of CS. The univariate predictors of the 16 minor events were peripheral arterial disease (OR 8.8 [2.7-28.5]; p<0.001), CS (OR 4.9 [1.7-14.2]; p=0.002), SMI (OR 3.7, [1.3-10.5]; p=0.009) and smoking (OR 3.2 [1.1-9.2]; p=0.024). In the multivariate analysis, arterial occlusive disease (p<0.001), smoking (p<0.036) and CS (p=0.044) were independent predictors of events. CONCLUSION Silent CS predict major cardiac events but also other cardiovascular events and are more common in diabetic patients > 65 years-old, of male gender and with > or =2 risk factors.

Multicentre, randomised, controlled study of the impact of continuous sub-cutaneous glucose monitoring (GlucoDay®) on glycaemic control in type 1 and type 2 diabetes patients

AIM This randomised study was designed to investigate the impact of continuous glucose monitoring (CGM) for 48h on glycaemic control with a 3-month follow-up in patients with type 1 (T1D) or type 2 (T2D) diabetes. METHODS A total of 48 patients with poor glycaemic control (HbA(1c): 8-10.5%) underwent CGM for 48h using the GlucoDay((R)) system (A. Menarini Diagnostics), after which they were randomly assigned to treatment adjustments based on either their CGM profile (CGM group) or their usual self-monitoring of blood glucose (SMBG group). HbA(1c) measurement and 48-h CGM were repeated 3 months later. RESULTS Altogether, 34 patients with either T1D (n=9) or T2D (n=25) completed the study; seven patients chose to leave the study, and seven patients in the CGM group were excluded because their baseline CGM graphs were not interpretable. HbA(1c) levels decreased significantly in the CGM group (n=14, -0.63+/-0.27%; P=0.023), but not in the controls (n=20, -0.28+/-0.21%; P=0.30). In T2D patients, the improvement associated with CGM vs SMBG was due to HbA(1c) decreases (mean: -0.63+/-0.34%; P=0.05 vs -0.31+/-0.29%; P=0.18, respectively). However, HbA(1c) did not change significantly with CGM in T1D patients. Comparisons of CGM data at baseline and after 3 months showed no significant changes in glucose control, glucose variability or hypoglycaemia. No major adverse events related to the GlucoDay system were reported. CONCLUSION This is the first randomised study showing that CGM improves glycaemic control in patients with T2D.

It is not yet the time to stop screening diabetic patients for silent myocardial ischaemia

Despite the intensified control of risk factors, silent myocardial ischaemia (SMI) is still a frequent complication of diabetes that is also associated with a higher risk of cardiac events. The objectives of this review are to summarize the importance of screening for SMI in a subset of asymptomatic diabetic patients. There is evidence that screening markedly improves the evaluation of cardiovascular risk compared with the usual risk scores. New markers, validated by large-scale studies, are needed to help in identifying the patients with silent coronary stenoses, thereby lowering the number of screened patients. Some indications of benefit with revascularization in patients with silent coronary stenoses are also available. Although it is not yet time to stop screening diabetic patients for SMI, such screening should focus on patients who are at high or intermediate cardiovascular risk. Guidelines need to be updated to increase the value of screening.

Markers for silent myocardial ischemia in diabetes. Are they helpful

Silent myocardial ischemia (SMI) and silent coronary stenoses (CS) are two to seven times more frequent in diabetic patients than in non-diabetic patients. In addition to this, they have a higher predictive value for cardiovascular events than the classical cardiovascular risk factors, either taken alone or combined. Coronary arterial disease is the leading cause of mortality and morbidity in the diabetic population. Altogether, these data suggest that screening for SMI and silent CS is an important issue. We assume that detecting SMI and silent CS improves patient management, and leads to optimised follow-up, action taken on nutrition, exercise and lifestyle, management of the cardiovascular risk factors, and revascularisation procedures whenever possible. However, screening for SMI and silent CS is expensive and may induce morbidity. Selecting the patients with a high a priori risk of SMI and silent CS is therefore of major concern. Carotid or lower limb peripheral arterial disease, proteinuria, male gender, an age greater than 60 years, and two or more cardiovascular risk factors among smoking, microalbuminuria, dyslipidemia, hypertension, a family history of premature cardiac disease, and cardiac autonomic neuropathy have been demonstrated to be the best current predictors of SMI and silent CS. New markers, such as adhesion molecules, Lp(a), inflammation parameters or homocysteine, and endothelium function assessment might be of further help in the future.

Fas/Fas-Ligand pathway is impaired in patients with type 2 diabetes. Influence of hypertension and insulin resistance

OBJECTIVES In type 2 diabetic patients with no cardiac history or symptoms, 1) to evaluate whether the soluble forms of Fas (sFas) and Fas-ligand (sFasL), involved in apoptosis, may be markers of silent coronary disease or related to hypertension or microangiopathic complications; 2) to examine the effect of short-term glycemic control on sFas and sFasL. METHODS (1) sFas and sFasL were measured with the ELISA method in 44 asymptomatic diabetic patients, 33 with hypertension, and with a normal myocardial scintigraphy (n=14), with silent myocardial ischemia (SMI) and without (n=15) or with (n=15) significant coronary stenoses; and in 14 controls; (2) sFas and sFasL were measured in 15 poorly controlled diabetic patients before and after 7 days of CSII treatment. RESULTS (1) sFas and sFasL differed in the four groups of patients (p=0.003 each). sFas was significantly higher in the patients with SMI without (p=0.035) and with coronary stenoses (p=0.002) than in the control group. sFasL was lower in the three groups of diabetic patients (p<0.05 each) than in control group. In the diabetic population, sFas correlated positively with hypertension (p=0.021), and sFasL negatively with hypertension (p=0.027) and HOMA index in the non-insulin treated patients (p=0.049); (2) sFas did not differ before or after CSII, and there was a marginal decrease in sFasL. CONCLUSION Fas-mediated apoptosis is involved in type 2 diabetes and might be associated with hypertension and/or its vascular consequences. sFasL might be affected by insulin resistance. sFas and sFasL are not effective markers of SMI.

Hemodynamic changes in postprandial state

Several experimental data suggest that single sugar intake may induce heart rate acceleration and blood pressure elevation as a result of sympathetic activation secondary to insulin response and from alterations in endothelial function due to activation of oxidative stress. These hemodynamic effects might be more marked in patients with arterial hypertension or metabolic disorders, in particular in hypertensive patients with diabetes. A high-fat load may also induce activation of oxidative stress and endothelial dysfunction. However, the long-term effect of repeated intake of single sugar and fat on blood pressure, oxidative stress, and endothelial function should be tested in controlled trials. On the contrary, a balanced mixed meal (50% carbohydrates) does not induce any significant blood pressure changes. Nevertheless, acarbose treatment is able to reduce hypertension incidence in patients with impaired glucose tolerance and to improve endothelial function. In elderly subjects, in particular with type 2 diabetes or with severe dysautonomia, sigle sugar intake may account for nonhypoglycemic postprandial dizziness.

P 15: Low serum levels of L-Selectin as markers of silent myocardial ischemia and endothelial dysfunction in type 2 diabetic patients

Introduction In a pilot study we previously suggested that a low serum level of soluble L-Selectin, a protein involved in leucocyte adhesion, might be a marker of coronary artery disease in type 2 diabetic patients (T2D). The aim was to confirm this result in a larger cohort and to explore the association with endothelial dysfunction. Patients and Methods L-Selectin was measured in 364 (230 men) asymptomatic patients with T2D for 13.3±7.0 years, 59.9±8.5 years old, with at least one associated cardiovascular risk factor: hypertension 77.1%, dyslipidemia 70.8%, smoking 22.8%, incipient nephropathy 40.8%, peripheral occlusive arterial disease 13.0%, cardiac autonomic neuropathy (assessed on three standard tests) 74.0%. Silent myocardial ischemia (SMI) was detected by stress myocardial scintigraphy in 135 patients, and 45 of them had significant coronary stenoses on angiography. Results L-Selectin levels were lower in the patients with than in those without SMI (788±218 vs 853±244 ng/ml, p Conclusion Serum levels of L-Selectin are low in T2D patients with SMI. This change may account for leucocytes adhesion on activated endothelium, as suggested by the negative correlation between L-Selectin and albuminuria. The association hypertension - cardiac autonomic neuropathy may play a role in endothelium dysfunction.

P 20: Coronary microvascular response to a coldpressor test and cardiac autonomic neuropathy in asymptomatic type 2 diabetic patients free of coronary stenoses

Background and aims The cold-pressor test (CPT) by inducing sympathetic stimulation and a subsequent rise in myocardial oxygen demand is expected to induce an increase in coronary blood flow and a dilation of normal epicardial coronary arteries. The aim of this study was in type 2 diabetic patients (T2Ds) free of coronary stenoses to analyse the influence of cardiac autonomic neuropathy (CAN) on the coronary response to CPT measured with a non invasive method based on trans-thoracic echography-doppler (NCT00685984). Materials and Methods We prospectively screened 118 T2Ds, without any cardiac history and fulfilling the criteria of the French guidelines, for silent myocardial ischemia (SMI: abnormal stress myocardial scintigraphy and/or echocardiography). A coronary angiography was performed in those with SMI. The distal inter-ventricular anterior coronary velocity (CV) was measured by trans-thoracic echo-doppler before and after CPT (one hand immersed in crushed ice for 120 s) in these patients and also in 16 control subjects. CAN was assessed using three standard tests (deep-breathing, lying-to-standing and Valsalva) and considered to be present if ≥2 tests were abnormal. Results CV before and after CPT could be measured reliably in 35 T2Ds free of coronary stenoses and with CAN function tests being performed and in all control subjects. CAN was found in 17 T2Ds. At baseline, T2Ds had higher heart rate, rate-pressure product (DP) and CV than controls (p Conclusion T2Ds without evidence of coronary artery disease but with impaired vagal cardiac tests exhibit at baseline some signs of relative increase in sympathetic activity. They have a lower increase in DP after CPT which is consistent with a lower sympathetic reactivity but this increase in myocardial oxygen demand resulting from sympathetic stimulation is sufficient to increase coronary blood flow.

P36 - Rôle de l’ischémie et de la neuropathie autonome cardiaque dans les altérations de la fonction myocardique chez les patients diabétiques asymptomatiques

Introduction L’alteration de la fonction myocardique du diabetique est d’origine multifactorielle mais peu d’etudes ont evalue le role de l’ischemie myocardique silencieuse (IMS), atteinte microcirculatoire eventuellement associee a des stenoses coronaires (SC), et de la neuropathie autonome cardiaque (NAC). Patients et methodes Nous avons realise une echocardiographie trans-thoracique chez 293 patients, diabetiques depuis 14 ± 7 ans, 172 hommes, 57,8 ± 8,8 ans, asymptomatiques au plan coronarien et sans insuffisance cardiaque clinique mais presentant d’autres facteurs de risque cardiovasculaire. La fonction systolique du ventricule gauche ; la fonction diastolique : E/A mitral, onde ea a l’anneau mitral, E/ea, Vp, E/Vp et 2 indices de performance precocement alteres : l’onde s a l’anneau mitral et l’index de Tei, ont ete mesurees. Une NAC a ete definie par ≥ 1 test anormal parmi 3 tests (respiration profonde, orthostatisme, Valsalva) evaluant la variabilite de la frequence cardiaque. Une scintigraphie myocardique et/ou une echographie cardiaque de stress permettait d’identifier l’IMS. Une coronarographie etait effectuee si l’une de ces epreuves non invasives etait anormale. Resultats Une IMS et une NAC etaient presentes respectivement chez 98 (33,6%) et 183 (62,5%) patients. La presence de SC en cas d’IMS (31 patients) n’etait pas associee a la presence d’une NAC. Les patients avec IMS et/ou NAC avaient une fonction systolique globale (fraction d’ejection : NAC-IMS-/NAC-IMS + / NAC + IMS-/NAC + IMS + 69±6/68±6/67±6/ 64±11% respectivement, p Conclusion Chez les diabetiques asymptomatiques a haut risque cardiovasculaire, l’association IMS/NAC participe a la degradation de la fonction systolique et de la relaxation ventriculaires gauches.

P8 Le diabète est un facteur de risque indépendant de récidive à distance d’un carcinome hépato-cellulaire unique traité par radiofréquence chez des cirrhotiques Child Pugh A

Introduction L’objectif de l’etude etait d’evaluer, chez des cirrhotiques Child Pugh A ayant eu un carcinome hepato-cellulaire (CHC) unique Materiels et Methodes 86 patients (41 diabetiques, 61 hommes), 65,3 ± 10,0 ans et cirrhotiques (alcool : 22, hepatite virale C : 48, hepatite virale B : 8, autres : 8) ont ete suivis pendant 2,6 ± 0,8 ans. La taille du CHC a l’inclusion etait de 22 ± 6 mm, le temps de prothrombine de 79 ± 14 %, l’albuminemie de 41 ± 4 g/l et l’alfa-foetoproteine > 100 ng/mL chez 12 patients. Resultats Un CHC a recidive a distance chez 40 patients ; 26 sont decedes et 14 ont ete transplantes. Apres analyse multivariee prenant en compte les facteurs predicteurs avec p Discussion Le stress oxydatif augmente et possiblement l’hyperinsulinisme pourraient en cas de diabete exercer des effets mitotiques et anti-apoptotiques. Conclusion Le diabete est un facteur de risque independant de recidive de CHC a distance d’un traitement initial par radiofrequence chez les cirrhotiques. La recidive de CHC est responsable d’une surmortalite.