A randomized trial of the impact of strict glycaemic control on myocardial diastolic function and perfusion reserve: a report from the DADD (Diabetes mellitus And Diastolic Dysfunction) study.

AIMS: Myocardial diastolic dysfunction (MDD) and impaired coronary flow reserve (CFR) are early signs of myocardial involvement in patients with diabetes. The important question of whether this may be reversed by glucose normalization has not been tested in a controlled clinical trial. We hypothesized that strict glycaemic control, particularly if insulin based, will improve MDD and CFR. METHODS AND RESULTS: Thirty-nine type 2 diabetes patients (mean age 61.0 +/- 7 years) with signs of diastolic dysfunction were randomly assigned to strict metabolic control by insulin (I-group; n = 21) or oral glucose lowering agents (O-group; n = 18). MDD and CFR were studied with Doppler-echocardiography including Tissue Doppler Imaging and myocardial contrast enhanced echocardiography. Fasting glucose (I-group = -2.2 +/- 2.1; O-group -1.5 +/- 0.8 mmol/L) and HbA(1c) were normalized (-0.6 +/- 0.4 and -0.7 +/- 0.4%, respectively) in both groups, but this did not significantly improve MDD in either of the groups (P = 0.65). There was no difference in CFR before and after improved glycaemic control. CONCLUSION: The hypothesis that strict glycaemic control would reverse early signs of MDD and improve CFR in patients with type 2 diabetes could not be confirmed, despite achieved normalization. Whether it is possible to influence a more pronounced diastolic dysfunction, particularly in less well-controlled diabetic patients, remains to be established.

Left atrial velocity vector imaging for the detection and quantification of left ventricular diastolic function in type 2 diabetes.

UNLABELLED: Left ventricular (LV) diastolic dysfunction (DD) is diagnosed by Doppler echocardiography (DE) and Tissue Doppler imaging (TDI). Velocity vector imaging (VVI) evaluates myocardial deformation (strain). We studied left atrial (LA) deformation and volumes by VVI in relation to established Doppler-derived indices of LV diastolic function in diabetic patients. MATERIAL: Using DE and TDI , 87 patients (males 49%; age 60+/-7 years) with type 2 diabetes mellitus were classified as having no (n=60), mild (n=13) or moderate (n=14) DD. RESULTS: LA volume was larger in moderate (72.3+/-22.4 ml) than in mild DD (58.8+/-16.1 ml; p=0.01) and no DD (57.9+/-16.0 ml; p=0.01). LA roof strain distinguished no DD from mild and moderate DD (p=0.0073). Systolic LA strain correlated to total emptying fraction (r=0.70, p<0.0001), and inversely to LA volume (r=-0.35, p=0.0009). A cross-validated analysis of no versus mild or moderate DD expressed by LA strain revealed a positive predictive value of 48% and negative of 84%. CONCLUSION: LA strain by VVI is impaired in patients with type 2 diabetes mellitus and mild or moderate LV DD. LA strain seems of value in distinguishing normal from abnormal diastolic function. VVI offers new information on regional LA function and LA volumes but has too limited discriminative power to detect early LV DD.

Long-term calcium antagonist treatment of human hypertension with mibefradil or amlodipine increases sympathetic nerve activity.

OBJECTIVES: Calcium antagonists are vasodilating drugs, which may cause reflex activation of the sympathetic nervous system with potentially untoward effects. We studied the effects of long-term treatment with amlodipine, a long-acting dihydropyridine-type calcium antagonist, and mibefradil, a phenylalkylamine-type calcium antagonist, on sympathetic nerve activity. METHODS: Fourteen patients with primary hypertension participated in a double-blind, cross-over study comparing the effects of 6 weeks of treatment with mibefradil 100 mg daily and amlodipine 10 mg daily. Heart rate, direct arterial blood pressure and cardiac output by echocardiography were registered. Global sympathetic activity was estimated using a [3H]noradrenaline isotope dilution method with arterial and venous sampling; cardiac sympathetic activity was assessed indirectly by heart rate variability and tissue velocity echocardiography. RESULTS: Both drugs lowered mean arterial pressure; the decrease was more pronounced with mibefradil (from 118 +/- 3 to 99 +/- 2 mmHg, compared to 118 +/- 3 to 104 +/- 2 mmHg for amlodipine, P < 0.01 between drugs). Mibefradil decreased heart rate (66 +/- 2 to 57 +/- 2 bpm), whereas amlodipine caused a slight increase (66 +/- 2 to 70 +/- 2 bpm; P < 0.001 between drugs) and tended to increase cardiac output. Noradrenaline spillover increased similarly with the two drugs, from 3.44 +/- 0.27 to 5.20 +/- 0.48 nmol/min per m2(P < 0.01) during mibefradil and to 5.72 +/- 0.49 nmol/min per m2 (P < 0.001) during amlodipine. There were minor effects on cardiac sympatho-vagal balance, but systolic and diastolic myocardial velocities were increased similarly by both drugs. CONCLUSIONS: Mibefradil and amlodipine treatment increase global sympathetic nerve activity similarly during long-term treatment, despite opposite effects on heart rate. Increases in myocardial velocities suggest concomitant cardiac sympathetic activation.

Ambulatory combined pH, bile and manometric monitoring of the oesophagus in asymptomatic healthy volunteers.

BACKGROUND: With the development of sophisticated equipment ambulatory studies of oesophageal motor function, pH and bilirubin have gained in popularity. The aim of the study was to present reference values for combined 24 h pH, bilirubin and manometric measurements of the oesophagus. METHODS: Twenty-six (15 male) healthy volunteers without symptoms of gastro-oesophageal reflux underwent a 24-h ambulatory oesophageal combined three-channel pressure, acid and bilirubin detection. RESULTS: The subjects were studied for a median of 20 h (16-22). The median per cent time with pH < 4 for the whole measured time was 3.1 (0.8-14; 5 and 95 percentiles). Bile was detected for a median of 0.05% (0.0-8.5; 5 and 95 percentiles) of the time. Eighty-one per cent of the contractions were peristaltic, 55% of which were complete. Of these, 53% had a pressure over 30 mmHg at all three pressure points, giving an efficient peristalsis in a median of 29% (13-46; 5 and 95 percentiles) of all registered contractile patterns. No difference between the genders could be observed. CONCLUSIONS: This study provides normative data for ambulatory oesophageal manometry, pH and bilirubin studies that can be used for comparing with patients with disease.

Hemodynamic and sympathoadrenal responses to mental stress during nitric oxide synthesis inhibition.

Cardiovascular and sympathoadrenal responses to a reproducible mental stress test were investigated in eight healthy young men before and during intravenous infusion of the nitric oxide (NO) synthesis inhibitor N-monomethyl-L-arginine (L-NMMA). Before L-NMMA, stress responses included significant increases in heart rate, mean arterial pressure, and cardiac output (CO) and decreases in systemic and forearm vascular resistance. Arterial plasma norepinephrine (NE) increased. At rest after 30 min of infusion of L-NMMA (0.3 mg.kg(-1).min(-1) iv), mean arterial pressure increased from 98 +/- 4 to 108 +/- 3 mmHg (P <0.001) because of an increase in systemic vascular resistance from 12.9 +/- 0.5 to 18.5 +/- 0.9 units (P <0.001). CO decreased from 7.7 +/- 0.4 to 5.9 +/- 0.3 l/min (P <0.01). Arterial plasma NE decreased from 2.08 +/- 0.16 to 1.47 +/- 0.14 nmol/l. Repeated mental stress during continued infusion of L-NMMA (0.15 mg.kg(-1).min(-1)) induced qualitatively similar cardiovascular responses, but there was a marked attenuation of the increase in mean arterial blood pressure, resulting in similar "steady-state" blood pressures during mental stress without and with NO blockade. Increases in heart rate and CO were attenuated, but stress-induced decreases in systemic and forearm vascular resistance were essentially unchanged. Arterial plasma NE increased less than during the first stress test. Thus the increased arterial tone at rest during L-NMMA infusion is compensated for by attenuated increases in blood pressure during mental stress, mainly through a markedly attenuated CO response and suppressed sympathetic nerve activity.