Systolic and diastolic left ventricular dysfunction in middle-aged asymptomatic non-insulin-dependent diabetics.

Radionuclide ventriculographic studies were performed at rest and during exercise in 15 middle-aged asymptomatic patients with non-insulin-dependent diabetes mellitus (NIDDM) whose mean age was 58.7 +/- 10.5 years (mean +/- SD), and in 10 age- and sex-matched normal control subjects. The patients had neither clinical evidence of cardiovascular diseases nor obvious perfusion defects during maximal exercise testing with thallium-201 myocardial scintigraphy. The average left ventricular ejection fraction (LVEF) at rest was 69.1 +/- 5.3% in the diabetic patients and 65.6 +/- 4.2% in the control subjects, and during exercise, the average LVEFs were 68.3 +/- 6.9% and 72.1 +/- 5.0%, respectively. The changes in LVEF during exercise were -0.7 +/- 7.6% in the diabetic group and +6.5 +/- 2.6% in the control group (p < 0.01). However, the filling fraction during the first third of diastole at rest was significantly less in the diabetic group than in the control group (p < 0.05), the time to peak filling rate (TPF) was longer, and the TPF/R-R, normalized by the R-R interval and expressed as a percentage, was greater in the NIDDM patients than in the control subjects. There was close correlation between the abnormal response of LVEF to exercise and the reduced early diastolic filling in the diabetic patients. We concluded that 1) not only the response of LVEF to exercise but also the early left ventricular diastolic filling at rest are impaired in middle-aged asymptomatic NIDDM patients, and 2) some common factors could cause dysfunction of both the systolic and diastolic left ventricles in NIDDM patients, possibly latent global myocardial ischemia or metabolic myocardial disturbances.     

Impaired left ventricular systolic function during exercise in middle-aged insulin-dependent and noninsulin-dependent diabetic subjects without clinically evident cardiovascular disease

Equilibrium radionuclide angiocardiography was performed on 19 men and 17 women with insulin-dependent diabetes mellitus (IDDM) and on 24 men and 15 women with noninsulin-dependent diabetes mellitus (NIDDM) and on 24 male and 24 female control subjects aged 46 to 67 years. All were without clinically evident cardiovascular disease. No significant differences were found in left ventricular (LV) ejection fraction at rest between men with IDDM (56 +/- 1%; mean +/- standard error of the mean) or NIDDM (58 +/- 1%) and control men (58 +/- 1%), whereas LV ejection fraction was higher in women with IDDM (63 +/- 1%; p less than 0.01) and NIDDM (64 +/- 2%; p less than 0.01) than in control women (58 +/- 1%). An abnormal LV ejection fraction response to dynamic exercise (an increase of less than 5% units or a decrease) was observed in 1 control man (4%), in 8 men with IDDM (42%, p less than 0.01) and in 10 men with NIDDM (42%, p less than 0.01). The respective figures were 4 (17%) for control women, 7 (44%, difference not significant) for women with IDDM and 10 (71%, p less than 0.01) for women with NIDDM. Abnormal LV ejection fraction response to exercise in diabetic patients was not related to the metabolic control of diabetes, presence of microangiopathy or abnormalities in the autonomic nervous function. Myocardial perfusion scintigraphy performed in 18 diabetic patients in whom LV ejection fraction decreased during exercise showed a reversible perfusion defect in only 5 (28%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial Dysfunction and Adrenergic Cardiac Innervation in Patients With Insulin-Dependent Diabetes Mellitus

Background. Insulin-dependent diabetes mellitus (IDDM) is associated with an increased incidence of heart failure due to several factors, and in some cases a specific cardiomyopathy has been suggested.Objectives. This study sought to assess the mechanisms of exercise-induced left ventricular (LV) dysfunction in asymptomatic patients with IDDM in the absence of hypertensive or coronary artery disease.Methods. Fourteen consecutive patients with IDDM were enrolled (10 men, 4 women; mean [±SD] age 28.5 ± 6 years); 10 healthy subjects matched for gender (7 men, 3 women) and age (28.5 ± 3 years) constituted the control group. LV volume, LV ejection fraction (LVEF) and end-systolic wall stress were calculated by two-dimensional echocardiography at rest and during isometric exercise. LV contractile reserve was assessed by post-extrasystolic potentiation (PESP) obtained by transesophageal cardiac electrical stimulation and dobutamine infusion. Myocardial iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy was performed to assess adrenergic cardiac innervation.Results. Diabetic patients were classified into group A (n = 7), with an abnormal LVEF response to handgrip (42 ± 7%), and group B (n = 7), with a normal response (72 ± 8%). Baseline LVEF was normal in both group A and B patients (60 ± 6% vs. 61 ± 7%, p = NS). In group A patients, the LV circumferential wall stress–LVEF relation showed an impairment in LVEF disproportionate to the level of LV afterload. No significant changes in LVEF occurred during dobutamine (60 ± 6% vs. 64 ± 10%, p = NS), whereas PESP significantly increased LVEF (60 ± 6% vs. 74 ± 6%, p < 0.001); PESP at peak handgrip normalized the abnormal LVEF (42 ± 7% vs. 72 ± 5%, p < 0.001); and MIBG uptake normalized for body weight or for LV mass was lower than that in normal subjects (1.69 ± 0.30 vs. 2.98 ± 0.82 cpm/MBq per g, p = 0.01) and group B diabetic patients (vs. 2.79 ± 0.94 cpm/MBq per g, p = 0.01). Finally, a strong linear correlation between LVEF at peak handgrip and myocardial MIBG uptake normalized for LV mass was demonstrated in the study patients.Conclusions. Despite normal contractile reserve, a defective blunted recruitment of myocardial contractility plays an important role in determining exercise LV dysfunction in the early phase of diabetic cardiomyopathy. This abnormal response to exercise is strongly related to an impairment of cardiac sympathetic innervation.     

Autonomic nervous function and its relationship to cardiac performance in middle-aged diabetic patients without clinically evident cardiovascular disease.

Autonomic nervous function was evaluated in 36 patients with insulin-dependent diabetes mellitus (IDDM), 39 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 48 control subjects, all without clinically evident cardiovascular disease. Valsalva ratio and heart rate variation during deep breathing were lower in both diabetic groups than in the control group. Autonomic nervous function score (ANFS) was more abnormal in patients with IDDM than in control subjects, but was not significantly increased in patients with NIDDM. There was a negative correlation between ANFS and left ventricular diastolic filling evaluated by echocardiography or peak heart rate during exercise in both diabetic groups. There were no correlations between ANFS and left ventricular systolic function at rest or during exercise in any of the groups. In conclusion, autonomic nervous function was abnormal in middle-aged diabetic patients, and it was associated with impaired left ventricular diastolic filling at rest and decreased heart rate response to exercise, but not with left ventricular systolic function.     

Knowledge profile and control in diabetic patients

Knowledge about diabetes was assessed using a previously described interactive computer-based questionnaire in 79 patients with insulin-dependent (IDDM) and 72 with non-insulin-dependent (NIDDM) diabetes mellitus routinely attending a single diabetic clinic. Simple linear correlation of total knowledge score with glycosylated haemoglobin (HbA1c) showed no significant relationship for either IDDM (r = 0.12: p = 0.18) or NIDDM (r = 0.15: p = 0.1). However, quintile grouping of knowledge scores showed the mean HbA1c to be significantly higher in the lowest scoring NIDDM quintile (10.6 +/- 0.5: +/- SE) with respect to the pooled mean of all the higher scoring quintiles (9.0 +/- 0.3) (p = 0.027). Mean HbA1c (9.6 +/- 0.5) was also higher in the least knowledgeable IDDM quintile than any other quintile group (range 8.8-9.0) but this was not significant with respect to the pooled mean of higher scoring patients (p greater than 0.1). The mean age of the lowest scoring IDDM quintile group (60.5 +/- 13.9 years) was significantly higher (p less than 0.01) than higher scoring IDDM groups (mean age range 36.5-43.3 years) but age was not significantly related to HbA1c in IDDM subjects. IDDM showed greater knowledge of diabetes than NIDDM but ignorance in key areas was unacceptably high in both diabetic subtypes, indicating that regular knowledge assessment and educational reinforcement may be essential for good diabetic control as well as patient safety, particularly in older IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Attenuation of Neutrophil and Endothelial Activation by Intravenous Morphine in Patients With Acute Myocardial Infarction

To investigate the effects of morphine on neutrophil and endothelial activation, we measured serum levels of intercellular adhesion molecule-1 (ICAM-1), L-selectin, and neutrophil endopeptidase 24.11 (NEP) in 38 patients with acute myocardial infarction (group 1) and 16 control subjects (group 2). In group 1, all the patients underwent blood sampling at initial presentation and 10 minutes later. Twenty of them had 3 mg of morphine administered intravenously immediately after the first sampling (group 1A) and the other 18 after a second sampling (group 1B). The serum levels of ICAM-1 and L-selectin were both significantly higher in groups 1A and 1B than in group 2. In group 1A, the ICAM-1 decreased significantly at second blood samplings (310 ± 28 vs 368 ± 30 ng/ml; p <0.001), whereas in group 1B there was no significant change in ICAM-1 (357 ± 33 vs 359 ± 26 ng/ml; p = NS). In group 1A, the L-selectin decreased significantly at second blood samplings (2.3 ± 1.2 mg/L, p <0.001 vs baseline), whereas in group 1B there was no significant change in L-selectin (3.9 ± 1.0 mg/L, p = NS vs baseline). There was no significant difference in baseline NEP activities between groups 1A and 1B (4.89 ± 1.22 vs 5.14 ± 1.57 nmol/mg protein; p = NS). However, the NEP activities at second blood samplings decreased significantly in group 1A (9.88 ± 1.86 nmol/mg protein, p <0.001 vs baseline), whereas no significant changes were observed in group 1B (5.09 ± 1.62 nmol/mg protein, p = NS vs baseline). In conclusion, morphine increased NEP activities and thus attenuated shedding of L-selectin and ICAM-1.     

Restricted coronary flow reserve in patients with mitral regurgitation improves after mitral reconstructive surgery

Objectives. The purpose of this study was to assess coronary flow characteristics in patients with chronic mitral regurgitation (MR).

Background. Coronary flow reserve (CFR) has been reported to be restricted in cases with left ventricular (LV) volume overload caused by aortic regurgitation and increased LV preload.

Methods. The study populations consisted of 31 patients with nonrheumatic chronic MR. Eleven with chest pain and normal coronary arteries served as control subjects. Phasic coronary flow velocities were obtained in the proximal segment of the angiographically normal left anterior descending coronary artery at rest and during hyperemia (0.14 mg/kg/min adenosine infusion intravenously) using a 0.014-in. (0.036 cm), 15-MHz Doppler guide wire. Coronary flow reserve was obtained from the ratio of hyperemic/baseline time-averaged peak velocity (APV). Thirteen cases who underwent mitral valve reconstructive surgery were also studied 1 month after surgery.

Results. Compared with control subjects, CFR was significantly reduced in cases with MR (2.1 ± 0.5 vs. 3.3 ± 0.6, respectively, p < 0.01) because baseline APV was significantly greater (28 ± 8 vs. 19 ± 6 cm/s, respectively, p < 0.01), although maximal hyperemic APV was not significantly different (56 ± 14 vs. 61 ± 16 cm/s, respectively, p = NS). Significant correlations were obtained between CFR and LV end-diastolic pressure (LVEDP) (r = 0.70, p < 0.01), LV mass index (r = 0.42, p < 0.01), LV end-diastolic volume (r = 0.38, p = 0.04) and MR volume (r = 0.39, p = 0.03), and stepwise regression analysis showed LVEDP was the most important determinant of CFR in MR (r² = 0.49, p < 0.0001). This restricted CFR improved significantly after mitral valve reconstructive surgery (2.1 ± 0.5 vs. 3.1 ± 0.6, respectively, p < 0.01) because of reduction of baseline APV (28 ± 8 vs. 21 ± 8 cm/s, respectively, p < 0.01).

Conclusions. Coronary flow reserve is limited in cases with MR because of elevation of baseline resting flow velocity. This reduction of CFR correlates well with increase in LV preload, mass and volume overload, especially with increase in LV preload, and this restricted CFR improves after mitral valve surgery.     

Effect of carvedilol on microcirculatory and glucose metabolic regulation in patients with congestive heart failure secondary to ischemic cardiomyopathy

In a randomized (2:1), double-blinded design study, we studied 25 patients with congestive heart failure (66 ± 9 years, ejection fraction 30 ± 7%) before and after 23-week treatment with the β blocker carvedilol 25 mg twice daily (n = 17) or placebo (n = 8) in addition to standard therapy. Using dynamic positron emission tomography, myocardial perfusion at rest and perfusion reserve after dipyridamole (0.56 mg/kg/min) were measured. Myocardial glucose uptake and plasma levels of catecholamines were also estimated. Carvedilol treatment reduced the rate-pressure product (8,781 ± 2,672 vs 6,342 ± 1,346, p <0.01) and improved ejection fraction (29 ± 7% vs 37 ± 11%, p <0.001), whereas no changes were observed in the control group. Perfusion at rest was unchanged in the placebo group (0.81 ± 0.17 vs 0.86 ± 0.23 ml/g/min, P = NS), whereas the carvedilol-treated group showed a significant reduction (0.88 ± 0.26 vs 0.75 ± 0.16 ml/g/min, p <0.05). Dipyridamole-induced hyperemia was significantly reduced after carvedilol treatment (1.51 ± 0.45 vs 1.31 ± 0.51 ml/g/min, p <0.001), whereas myocardial perfusion reserve was unaltered. Carvedilol did not alter myocardial glucose uptake (0.33 ± 0.14 vs 0.32 ± 0.12 μmol/g/min, P = NS) or the plasma catecholamines levels. We therefore conclude that in patients with congestive heart failure, carvedilol reduced resting and hyperemic perfusion. No effect on glucose uptake or catecholamine levels was observed. The reduced perfusion at rest must reflect reduced perfusion demand and thereby a higher threshold for myocardial ischemia and protection against myocardial damage or malignant arrhythmia. These effects may serve as a pathophysiologic explanation for the reduced mortality in patients with congestive heart failure who receive carvedilol.     

Prognostic Value of Dobutamine Stress Echocardiography in Patients Undergoing Diagnostic Coronary Arteriography

There are only a few studies addressing the prognostic value of dobutamine stress echocardiography in patients with suspected coronary artery disease and none have assessed its value compared with coronary arteriography. Accordingly, graded dobutamine stress echocardiography was performed in 121 patients who underwent coronary arteriography based on symptoms and the findings of treadmill exercise electrocardiography. During the follow-up period of mean (SD) months (15 ± 9) there were 41 cardiac events (death [n = 5], acute myocardial infarction [n = 2], unstable angina [n = 29], and congestive heart failure [n = 5]). There were a greater number of patients with inducible wall motion abnormality (88%) on dobutamine stress with cardiac events compared with those without (55%, p <0.001). The wall motion score indexes at rest (1.6 ± 0.6) and at peak stress (2.1 ± 0.8) were worse in patients with cardiac events compared with those without (1.2 ± 0.3, p <0.001 and 1.5 ± 0.6, p <0.001, respectively). When multivariate analysis was performed using clinical, exercise, echocardiographic, and coronary arteriographic data the independent predictors of cardiac events were exercise duration (p = 0.01), presence of inducible wall motion abnormality (p = 0.03), and wall motion score index at peak stress (p <0.001). Thus, dobutamine stress echocardiography is a powerful predictor of future cardiac events in patients undergoing exercise testing and coronary arteriography for evaluation of chest pain and is superior to both exercise electrocardiography and coronary arteriography for the prediction of subsequent cardiac events.

Graded dobutamine stress echocardiography was performed in 121 patients undergoing diagnostic coronary arteriography for suspected coronary artery disease based on symptoms and findings of exercise electrocardiography. Stepwise Cox regression analysis using clinical, exercise electrocardiographic, echocardiographic, and coronary arteriography variables revealed that wall motion score index at peak stress (p <0.001), inducible ischemia (p = 0.03), and exercise duration (p = 0.04) were the only independent predictors of cardiac events.     

Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study

OBJECTIVES

Evaluate the safety, tolerability and preliminary efficacy of intracoronary (IC) basic fibroblast growth factor (bFGF, FGF-2).

BACKGROUND

FGF-2 is a heparin-binding growth factor capable of inducing functionally significant angiogenesis in animal models of myocardial ischemia.

METHODS

Phase I, open-label dose-escalation study of FGF-2 administered as a single 20-min infusion in patients with ischemic heart disease not amenable to treatment with CABG or PTCA.

RESULTS

Fifty-two patients enrolled in this study received IC FGF-2 (0.33 to 48 μg/kg). Hypotension was dose-dependent and dose-limiting, with 36 μg/kg being the maximally tolerated dose. Four patients died and four patients had non-Q-wave myocardial infarctions. Laboratory parameters and retinal examinations showed mild and mainly transient changes during the 6-month follow-up. There was an improvement in quality of life as assessed by Seattle Angina Questionnaire and improvement in exercise tolerance as assessed by treadmill exercise testing (510 ± 24 s at baseline, 561 ± 26 s at day 29 [p = 0.023], 609 ± 26 s at day 57 (p < 0.001), and 633 ± 24 s at day 180 (p < 0.001), overall p < 0.001). Magnetic resonance (MR) imaging showed increased regional wall thickening (baseline: 34 ± 1.7%, day 29: 38.7 ± 1.9% [p = 0.006], day 57: 41.4 ± 1.9% [p < 0.001], and day 180: 42.0 ± 2.3% [p < 0.001], overall P = 0.001) and a reduction in the extent of the ischemic area at all time points compared with baseline.

CONCLUSIONS

Intracoronary administration of rFGF-2 appears safe and is well tolerated over a 100-fold dose range (0.33 to 0.36 μk/kg). Preliminary evidence of efficacy is tempered by the open-label uncontrolled design of the study.     

Coronary dilatory capacity in idiopathic dilated cardiomyopathy: Analysis of 16 patients

Hemodynamic function and overall coronary blood flow (argon technique) were measured in 16 patients with idiopathic dilated cardiomyopathy (IDC) and in 12 patients without detectable heart disease (control subjects) referred for precordial pain. In patients with IDC, coronary blood flow was normal at rest (78 ± 17 ml/100 g·min versus 78 ± 9 in control subjects). During maximal inducible coronary vasodilation (dipyridamole, 0.5 mg/kg), coronary blood flow was significantly reduced (142 ± 38 ml/100 g · min versus 301 ± 64 in control subjects; p < 0.001). Consequently, obtainable minimal coronary resistance was increased in IDC (0.54 ± 0.20 mm Hg/ml/100 g · min versus 0.23 ± 0.04 in control subjects; p < 0.001). In patients with IDC, left ventricular (LV) end-diastolic pressure was significantly increased (19 ± 11 mm Hg versus 6 ± 3 in control subjects; p < 0.005), and the LV ejection fraction was diminished (36 ± 11% versus 72 ± 3% in control subjects; p < 0.001). In patients with IDC, LV end-diastolic pressure correlated significantly with the obtained minimal coronary resistance after application of dipyridamole (r = 0.85; p < 0.001). LV catheter biopsy specimens revealed no alterations in myocardial microvasculature. Thus, coronary dilatory capacity is impaired in patients with IDC, due partially to an increase in extravascular component of coronary resistance.     

Low hot pain threshold predicts shorter time to exercise-induced angina: results from the psychophysiological investigations of myocardial ischemia (PIMI) study

OBJECTIVES

The purpose of this study was to test whether cutaneous thermal pain thresholds are related to anginal pain perception.

BACKGROUND

Few ischemic episodes are associated with angina; symptoms have been related to pain perception thresholds.

METHODS

A total of 196 patients with documented coronary artery disease underwent bicycle exercise testing and thermal pain testing. The Marstock test of cutaneous sensory perception was administered at baseline after 30 min of rest on two days and after exercise and mental stress. Resting hot pain thresholds (HPTs) were averaged for the two baseline visits and divided into two groups: 1) average HPT <41°C, and 2) average HPT ≥41°C, to be clearly indicative of abnormal hypersensitivity to noxious heat.

RESULTS

Patients with HPT <41°C had significantly shorter time to angina onset on exercise testing than patients with HPT ≥41°C (p < 0.04, log-rank test). Heart rates, systolic blood pressure and rate–pressure product at peak exercise were not different for the two groups. Resting plasma beta-endorphin levels were significantly higher in the HPT <41°C group (5.9 ± 3.7 pmol/liter vs. 4.7 ± 2.8 pmol/liter, p = 0.02). Using a Cox proportional hazards model, patients with HPT <41°C had an increased risk of angina (p = 0.03, rate ratio = 2.0). These differences persisted after adjustment for age, gender, depression, anxiety and history of diabetes or hypertension (p < 0.01).

CONCLUSIONS

Occurrence of angina and timing of angina onset on an exercise test are related to overall hot pain sensory perception. The mechanism of this relationship requires further study.     

Glucose and insulin responses to intravenous glucose challenge in relatives of Nigerian patients with non-insulin-dependent diabetes mellitus

We analysed blood insulin and glucose concentrations before and during frequently sampled intravenous glucose tolerance tests (FSIGT) in 2 groups of Nigerian subjects: (A) Control group (n = 18), without a positive family history of diabetes mellitus, and (B) Experimental group (n = 16), comprising age-, sex- and body mass-matched first-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM). In comparison with Group A subjects, those in Group B had: (i) higher fasting plasma glucose level (mean ± S.E.M., 4.1 ± 0.1 vs. 3.8 ± 0.11 mmol/l, P < 0.05); (ii) similar fasting serum insulin levels (6.7 ± 5.0 vs. 5.8 ± 5.6 mU/l, P = NS); (iii) lower mean incremental area under the first-phase (t = 0–10 min) post-glucose challenge insulin curve (376.9 ± 8.8 vs. 435.6 ± 5.6 mU/min l⁻¹, P < 0.05); (iv) increased incremental area under the second-phase (t = 10–182 min) post-glucose challenge insulin curve (432.9 ± 11.5 vs. 161.3 ± 8.7 mU/min l⁻¹, P < 0.05); (v) reduced K_G rate constant of glucose elimination (0.97 ± 0.12 vs. 1.41 ± 0.12%/min, P < 0.05). These results suggest that the subjects with a positive family history of NIDDM have a reduced beta-cell insulin secretory reserve (from reduced first-phase insulin response), tendency to rebound hyperinsulinemia during the latter phase of the insulin secretory response, a degree of tissue insulin insensitivity (as evident from high fasting plasma glucose despite similar insulin levels) and a diminished glucose disposal rate, in comparison with subjects without a family history of NIDDM. These features predict subsequent development of diabetes and suggest that as in Caucasians, first-degree relatives of Nigerian patients with NIDDM are at greater risk for future development of the disease.     

Improvement of left ventricular dysfunction during exercise by walking in patients with successful percutaneous coronary intervention for acute myocardial infarction.

A growing body of evidence suggests that walking reduces the incidence of coronary events, so the present study investigated whether walking influences left ventricular function in 30 patients with acute myocardial infarction (AMI) who had undergone successful percutaneous coronary intervention (PCI). The patients were randomly assigned to either a 3-month exercise training program of walking (group W, n=15) or a control group (group C, n=15). At both the beginning and end of the study, patients underwent exercise stress echocardiography to determine left ventricular ejection fraction (LVEF) at rest and during exercise. At baseline, there was no difference in LVEF at rest or during exercise between the two groups. After 3 months, LVEF during exercise was significantly improved compared with at rest in group W (61+/-3% during exercise vs 57+/-5% at rest, p<0.01), whereas no difference was observed between the LVEF at rest and that during exercise in group C (54+/-5% at rest vs 52+/-7% during exercise, NS). Walking may be beneficial for improving left ventricular function during exercise in patients with AMI.     

Myocardial flow reserve in patients with a systemic right ventricle after atrial switch repair

OBJECTIVES

The purpose of this study was to assess myocardial blood flow (MBF) and flow reserve in systemic right ventricles (RV) in long-term survivors of the Mustard operation.

BACKGROUND

There is a high prevalence of systemic RV dysfunction and impaired exercise performance in long-term survivors of the Mustard operation. A mismatch between myocardial blood supply and systemic ventricular work demand has been proposed as a potential mechanism.

METHODS

We assessed MBF at rest and during intravenous adenosine hyperemia in 11 long-term survivors of a Mustard repair (age 18 ± 5 years, median age at repair 0.7 years, follow-up after repair 17 ± 5 years) and 13 healthy control subjects (age 23 ± 7 years), using N-13 ammonia and positron emission tomography imaging.

RESULTS

There was no difference in basal MBF between the systemic RV of survivors of the Mustard operation and the systemic left ventricle (LV) of healthy control subjects (0.80 ± 0.19 vs. 0.74 ± 0.15 ml/g/min, respectively, P = NS). However, the hyperemic flows were significantly lower in systemic RVs than they were in systemic LVs (2.34 ± 0.0.69 vs. 3.44 ± 0.62 ml/g/min respectively, p < 0.01). As a result, myocardial flow reserve was lower in systemic RVs than it was in systemic LVs (2.93 ± 0.63 vs. 4.74 ± 1.09, respectively, p < 0.01).

CONCLUSIONS

Myocardial flow reserve is impaired in systemic RVs in survivors of the Mustard operation. This may contribute to systemic ventricular dysfunction in these patients.     

Impaired Myocardial Vasodilation During Hyperemic Stress With Dipyridamole in Hypertriglyceridemia

Objectives. This study sought to investigate the specific role of hypertriglyceridemia in the myocardial hyperemic stress with dipyridamole/rest flow ratio (MDR).

Background. Reduced MDR has been reported in hypercholesterolemic patients without evidence of ischemia. However, the specific role of hypertriglyceridemia in MDR has not been studied.

Methods. Fifteen nondiabetic normocholesterolemic hypertriglyceridemic patients and 13 age-matched control subjects were studied. Myocardial blood flow (MBF) during dipyridamole administration and baseline MBF in hypertriglyceridemic patients and control subjects were measured using positron emission tomography and nitrogen-13 ammonia, after which the MDR was calculated.

Results. Baseline MBF (ml/min per 100 g heart weight) in hypertriglyceridemic patients (mean ± SD 73.6 ± 24.1) did not differ significantly from that in control subjects (81.6 ± 37.2). MBF during dipyridamole loading in hypertriglyceridemic patients (198 ± 106) was significantly reduced compared with that in control subjects (313 ± 176, p < 0.05), as was the MDR (2.71 ± 1.07 vs. 3.73 ± 1.14, respectively, p < 0.05). Spearman rank-order correlation analysis showed a significant relation between plasma triglyceride concentration and MDR (r = −0.466, asymptotic SE 0.157, p = 0.0125); however, no such significant relation was seen between total plasma cholesterol concentration and MDR (r = −0.369, asymptotic SE 0.130, p = 0.059).

Conclusions. Impaired myocardial vasodilation was suggested in hypertriglyceridemic patients without symptoms and signs of ischemia.     

Scintigraphic Assessment of Regionalized Defects in Myocardial Sympathetic Innervation and Blood Flow Regulation in Diabetic Patients With Autonomic Neuropathy

Objectives. This study sought to evaluate whether regional sympathetic myocardial denervation in diabetes is associated with abnormal myocardial blood flow under rest and adenosine-stimulated conditions.

Background. Diabetic autonomic neuropathy (DAN) has been invoked as a cause of unexplained sudden cardiac death, potentially by altering electrical stability or impairing myocardial blood flow, or both. The effects of denervation on cardiac blood flow in diabetes are unknown.

Methods. We studied 14 diabetic subjects (7 without DAN, 7 with advanced DAN) and 13 nondiabetic control subjects without known coronary artery disease. Positron emission tomography using carbon-11 hydroxyephedrine was used to characterize left ventricular cardiac sympathetic innervation and nitrogen-13 ammonia to measure myocardial blood flow at rest and after intravenous administration of adenosine (140 μg/kg body weight per min).

Results. Persistent sympathetic left ventricular proximal wall innervation was observed, even in advanced neuropathy. Rest myocardial blood flow was higher in the neuropathic subjects (109 ± 29 ml/100 g per min) than in either the nondiabetic (69 ± 8 ml/100 g per min, p < 0.01) or the nonneuropathic diabetic subjects (79 ± 23 ml/100 g per min, p < 0.05). During adenosine infusion, global left ventricular myocardial blood flow was significantly less in the neuropathic subjects (204 ± 73 ml/100 g per min) than in the nonneuropathic diabetic group (324 ± 135 ml/100 g per min, p < 0.05). Coronary flow reserve was also decreased in the neuropathic subjects, who achieved only 46% (p < 0.01) and 44% (p < 0.01) of the values measured in nondiabetic and nonneuropathic diabetic subjects, respectively. Assessment of the myocardial innervation/blood flow relation during adenosine infusion showed that myocardial blood flow in neuropathic subjects was virtually identical to that in nonneuropathic diabetic subjects in the distal denervated myocardium but was 43% (p < 0.05) lower than that in the nonneuropathic diabetic subjects in the proximal innervated segments.

Conclusions. DAN is associated with altered myocardial blood flow, with regions of persistent sympathetic innervation exhibiting the greatest deficits of vasodilator reserve. Future studies are required to evaluate the etiology of these abnormalities and to evaluate the contribution of the persistent islands of innervation to sudden cardiac death complicating diabetes.     

Postprandial cholesteryl ester transfer and high density lipoprotein composition in normotriglyceridemic non-insulin-dependent diabetic patients

Altered postprandial HDL metabolism is a possible cause of defective reverse cholesterol transport and increased cardiovascular risk in diabetic patients with a normal fasting lipoprotein profile. Ten normolipidemic, normoponderal non-insulin dependent diabetes mellitus (NIDDM) patients and seven controls received a 980 kcal meal containing 78 g lipids with 100000 IU vitamin A. Chylomicron clearance was not different, but area under the curve (AUC) for retinyl palmitate in chylimicron-free serum (remnant clearance) was greater in patients (P < 0.02). LCAT activity increased postprandially to the same extent in both groups. In control subjects, cholesteryl ester transfer protein (CETP) activity (CETA) also increased by 20% (P < 0.01 at 6 h) in parallel with a 20% decrease in HDL₂-CE (r= −0.55, P = 0.009). In NIDDM patients, on the contrary, CETA which was 35% higher in the fasting state (P < 0.005), decreased postprandially yet HDL₂-CE remained unchanged. Postprandial HDL₃ of controls were enriched with phospholipid (PL) (30.3 ± 2.6% at 6 h) with respect to fasting (25.6 ± 2.5%, P < 0.01) and to NIDDM-HDL₃ (25.8 ± 1.7% at 6 h, P < 0.01). These results show that variation in plasma CETA has little impact on HDL₂-CE in NIDDH subjects. They support the concept that, in controls, the combined enrichment of HDL₃ with PL, increased LCAT and CETA create the conditions for stimulation of cell cholesterol efflux and CE transfer to apo B lipoproteins. In NIDDM, because of the lesser HDL₃ enrichment with PL and of the inverse trend of CETA, these conditions fail to occur, depriving the patients of a potentially efficient mechanism of unesterified cholesterol (UC) clearance, despite their strictly normal preprandial profile.     

The frequency and severity of retinopathy are related to HbA1c values after, but not at, the diagnosis of NIDDM

OBJECTIVES: To examine the relationship between previous glycaemic exposure and prevalence of retinopathy 8 years after diagnosis of diabetes in 58 islet cell antibodies (ICA)-negative noninsulin-dependent diabetes mellitus (NIDDM) patients and in a group of 14 ICA-positive 'NIDDM' and insulin-dependent diabetes mellitus (IDDM) patients. DESIGN AND METHODS: The Wisconsin retinopathy scale was used to assess the retinopathy which was graded into mild, moderate and severe nonproliferative diabetic retinopathy (NPDR), or proliferative retinopathy (PDR). The frequency and severity of retinopathy was related to HbA1c levels at diagnosis, and 3 and 5 years later. RESULTS: Thirty of the 58 ICA-negative NIDDM patients (52%) but only 2 of the 14 ICA-positive 'NIDDM' or IDDM patients (14%) had mild-moderate-severe NPDR 8 years after diagnosis (P = 0.02). None had PDR. Retinopathy 8 years after diagnosis in NIDDM (= 58 ICA-negative patients) was correlated with the degree of glycaemic control (HbA1c levels) at 3 and 5 years after diagnosis, but not to HbA1c levels at diagnosis. The relative risk for a higher average HbA1c (per percentage) at 3 and 5 years was 1.56 for any retinopathy vs. no retinopathy (95% confidence interval 1.1-2.2; P = 0.01) and 1.68 for moderate to severe NPDR in comparison with no DR and mild NPDR (95% confidence interval 1.0-2.8; P = 0.04). CONCLUSIONS: Retinopathy after 8 years of diabetes in NIDDM patients was associated with impaired glycaemic control during previous years but not with glycaemic control at baseline. Good glycaemic control may prevent retinopathy in patients with NIDDM.     

Glycemic control and coagulation inhibitors in diabetic patients.

OBJECTIVE: To investigate the plasma antigenic levels and functional activities of coagulation inhibitors in poorly controlled diabetic patients and the possible effect of good glycemic control on these parameters. RESEARCH DESIGN AND METHODS: Both functional activities and plasma antigenic levels of coagulation inhibitors (antithrombin III, heparin cofactor II, protein C, and protein S) and plasma levels of C4b-binding protein were measured in 28 diabetic patients (13 males, 15 females; 2 IDDM, 26 NIDDM; median age 56.5 years; median duration of diabetes 5.5 years) with poor glycemic control (median HbA(1c) 11.8%). Twenty-three healthy subjects were enrolled as controls. Following a 3-month intensification of antihyperglycemic therapy, good glycemic control (HbA(1c) <8%) was achieved in 17 patients, and the plasma levels of the same parameters during this period were compared with baseline values. RESULTS: Functional activities and plasma antigenic levels of coagulation inhibitors were comparable in poorly controlled diabetic patients and healthy subjects. In patients achieving good control after 3 months, there was a significant reduction in plasma antigenic levels of protein S (p = 0.005) and C4b-binding protein (p = 0.03); however, no difference could be observed in other parameters. HbA(1c) did not show any correlation with plasma antigenic levels or functional activities of coagulation inhibitors either at baseline or at 3 months of good glycemic control. CONCLUSIONS: Our findings suggest that in poorly controlled diabetic patients, coagulation inhibitors are not different from healthy controls. Short-term good glycemic control may not exert a profound effect on coagulation inhibitors except protein S and its binding protein, C4b-binding protein.