Disturbances in myocardial diastolic and vascular function with the emphasis on type 2 diabetes : Diagnostic and therapeutic opportunities

Background and aims Cardiovascular involvement is common in diabetes and diastolic myocardial and endothelial dysfunction are early signs. The prognosis is serious and tools for early detection and a search for improved management strategies are important. This thesis explores tools for the early detection of myocardial involvement and examines whether intensive glucose control could improve diastolic and endothelial dysfunction in patients with type 2 diabetes mellitus. Study I In comparison with mitral pulse wave Doppler, Tissue Doppler Imaging (TDI), a relatively pre-load independent technique, may improve the early identification of patients with diastolic dysfunction. Fifteen controls without heart failure, 30 patients with heart failure, were studied, 15 patients with diastolic left ventricular dysfunction and 15 with systolic left ventricular dysfunction. All the patients with diastolic heart failure were identified by mitral pulse wave Doppler or TDI, but only 11 were identified by atrio-ventricular plane displacement. The number of false positive patients were eight, ten and nine, respectively (p<0.01, p<0.05 and NS) for each of the three methods. Study II Eighty-seven patients with type 2 diabetes classified as having no (n=60), mild (n=13) or moderate (n=14) left ventricular diastolic dysfunction by Doppler echocardiography and TDI were investigated with Velocity Vector Imaging (VVI) which evaluates myocardial deformation (strain). Left atrial volume was larger in patients with moderate diastolic dysfunction compared with mild or no diastolic dysfunction (p=0.01). Left atrial roof strain distinguished no diastolic dysfunction from mild and moderate diastolic dysfunction (p=0.0073). Systolic left atrial strain correlated to total emptying fraction (r=0.70, p<0.0001) and inversely to left atrial volume (r=-0.35, p=0.0009). Studies III-IV Thirty-nine patients with type 2 diabetes and signs of diastolic dysfunction but no other cardiovascular disease manifestations were randomly assigned to glucose normalisation by insulin (I-group; n=21) or oral glucose-lowering agents (O-group; n=18). Myocardial diastolic dysfunction and coronary flow reserve were studied with Doppler echocardiography, including TDI and myocardial contrast-enhanced echocardiography. Fasting glucose and HbA1c were normalised in both groups, but this did not significantly influence myocardial diastolic dysfunction in either group (p=0.65). There was no difference in coronary flow reserve before and after improved glycaemic control. Twenty-two of the patients (I-group n=10; O-group n=12) were also investigated in terms of endothelial function and skin microcirculation by brachial artery flowmediated dilatation (FMD) and laser Doppler fluxmetry respectively. Glycaemic normalisation did not improve microcirculation. A reduction in FMD from 6.0 ± 2.2 to 4.7 ± 3.0% was observed in the I-group (p=0.037), but there was no change in the O-group (4.3±2.3 to 4.7±3.3%; p=0.76). The between-group difference was not significant (p=0.12). Conclusions TDI is useful for diagnosing diastolic myocardial dysfunction, with accuracy similar to that of conventional echocardiography including mitral pulse wave Doppler flow. Left atrial deformation, measured as regional and overall systolic strain, is impaired in patients with type 2 diabetes mellitus and mild to moderate left ventricular diastolic dysfunction and offers new information on regional LA function and LA volumes. Further, it may add to traditional Doppler echocardiography measurements for diagnosis of diastolic dysfunction. The hypothesis that improved glycaemic control would reverse early signs of myocardial diastolic and endothelial dysfunction in patients with type 2 diabetes was not proven. Whether it is possible to influence more pronounced dysfunction, particularly in patients with less well-controlled and long-standing diabetes, remains to be further explored in controlled clinical trials

A Survey of Empirical Results on Program Slicing

International audienceBACKGROUND:Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.METHODS:This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS:Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).INTERPRETATION:Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding