[show abstract][hide abstract] ABSTRACT: In addition to diabetes mellitus, less severe abnormalities of glucose and insulin metabolism may be related to functional status in patients with heart failure. We examined the relationship of hyperglycaemia (> or =6.1 mmol. l(-1)) and hyperinsulinaemia (> or =11.2 mU. l(-1)) to functional status and cardiac function in patients with heart failure.
Fasting plasma glucose and insulin levels were obtained in 663 heart failure patients. The average left ventricular ejection fraction was 0.28+/-0.07, 63% were in New York Heart Association Functional Class (NYHA-FC) I/II and 37% were in NYHA-FC III/IV. Twenty seven percent had diabetes mellitus, but an additional 8% had undiagnosed diabetes mellitus (glucose > or =7 mmol. l(-1)) and 9% had glucose levels between 6.1 and 7 mmol. l(-1), so that a total of 43% (287) of patients had elevated glucose levels (> or =6.1 mmol. l(-1)). In general, more diabetic patients had NYHA-FC III/IV symptoms, shorter 6 min walk distances, but similar left ventricular ejection fractions compared to non-diabetic patients. The non-diabetic patients in NYHA-FC III/IV had higher glucose and insulin levels than patients in NYHA-FC I/II (6.3+/-0.2 vs 5.6+/-0.1 mmol. l(-1), P<0.001 and 19.6+/-2.3 vs 10. 2+/-0.6 mU. l(-1), P<0.001). Non-diabetic patients with elevated glucose levels had shorter 6 min walk distances compared to those with normal glucose levels (368.2+/-8 m vs 389.+/-4 m, P=0.02), however, left ventricular ejection fraction was similar.
Glucose abnormalities are extremely common in heart failure patients (43% of patients). Diabetes mellitus and hyperglycaemia or hyperlinsulinaemia in non-diabetic patients were related to worse symptomatic status but not worsening left ventricular ejection fraction compared to patients with normal glucose and insulin levels.
European Heart Journal 08/2000; 21(16):1368-75. · 14.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine whether up-regulation of AT(1) and AT(2) receptors occurred in hypertrophied myocytes after infarction and whether AT(2) played a role in stretch-mediated apoptosis, left ventricular myocytes were dissociated from the surviving portion of the wall 8 days after coronary occlusion and cardiac failure in rats. Control cells were obtained from sham-operated animals. Myocytes were stretched in an equibiaxial stretch apparatus and angiotensin II (Ang II) formation and cell death were measured 3 and 12 hours later. AT(1) and AT(2) proteins were evaluated in freshly isolated myocytes and after stretch. The effects of AT(1) and AT(2) antagonists on stretch-induced Ang II synthesis and apoptosis were also established. Myocardial infarction increased AT(1) and AT(2) in myocytes and stretch further up-regulated these receptors. Ang II levels were higher in postinfarcted myocytes and this peptide increased with the duration of stretch in both groups of cells. Similarly, apoptosis increased with time in control and postinfarcted myocytes. Absolute values of Ang II and apoptosis were greater in myocytes from infarcted hearts at 3 and 12 hours after stretch. Addition of AT(1) blocker to cultures inhibited stretch-activated apoptosis in both myocyte populations as well as the generation of Ang II in postinfarcted myocytes. In contrast, AT(2) antagonists had no impact on these cellular events. In conclusion, Ang II stimulated cell death through AT(1) receptor activation, whereas ligand binding to AT(2) receptor did not alter Ang II concentration and apoptosis in normal and postinfarcted hypertrophied myocytes.
American Journal Of Pathology 06/2000; 156(5):1663-72. · 4.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine whether myocyte death and angiotensin II (AT II) formation are implicated in the development of diabetic cardiomyopathy, rats were injected with streptozotocin, and apoptosis and necrosis were measured at 3, 10, and 28 days. Expression of the components of the renin-angiotensin system (RAS) and AT II levels were assessed at 3 days. The percentage of AT II-labeled myocytes and the number and distribution of AT II sites in myocytes were measured at 3 and 10 days. The effects of AT1 blockade on local RAS and cell death were examined at 3 days. Diabetes was characterized by myocyte apoptosis that peaked at 3 days and decreased at 10 and 28 days, in spite of high concentrations of blood glucose. Cell necrosis was absent throughout. Angiotensinogen, renin, and AT1 receptor increased in myocytes from diabetic rat hearts, while angiotensin-converting enzyme and AT2 remained constant. AT II quantity increased severalfold, as did the fraction of AT II positive cells and the number of AT II sites per myocyte. However, AT II labeling decreased at 10 days, which paralleled the reduction in myocyte death. AT1 antagonist inhibited upregulation of this receptor and angiotensinogen, which prevented AT II synthesis and myocyte death at their peaks with diabetes. An aggregate 30% myocyte loss and a 14% increase in the volume of viable cells were found in diabetic rats at 28 days. Thus diabetic cardiomyopathy may be viewed as an AT II-dependent process in which that peptide plays a critical role in myocyte death and hypertrophy.
[show abstract][hide abstract] ABSTRACT: We investigated the effects of candesartan (an angiotensin II antagonist) alone, enalapril alone, and their combination on exercise tolerance, ventricular function, quality of life (QOL), neurohormone levels, and tolerability in congestive heart failure (CHF).
Seven hundred sixty-eight patients in New York Heart Association functional class (NYHA-FC) II to IV with ejection fraction (EF) <0.40 and a 6-minute walk distance (6MWD) <500 m received either candesartan (4, 8, or 16 mg), candesartan (4 or 8 mg) plus 20 mg of enalapril, or 20 mg of enalapril for 43 weeks. There were no differences among groups with regard to 6MWD, NYHA-FC, or QOL. EF increased (P=NS) more with candesartan-plus-enalapril therapy (0.025+/-0.004) than with candesartan alone (0.015+/-0.004) or enalapril alone(0.015+/-0.005). End-diastolic (EDV) and end-systolic (ESV) volumes increased less with combination therapy (EDV 8+/-4 mL; ESV 1+/-4 mL; P<0.01) than with candesartan alone (EDV 27+/-4 mL; ESV 18+/-3 mL) or enalapril alone (EDV 23+/-7 mL; ESV 14+/-6 mL). Blood pressure decreased with combination therapy (6+/-1/4+/-1 mm Hg) compared with candesartan or enalapril alone (P<0.05). Aldosterone decreased (P<0.05) with combination therapy (23.2+/-5.3 pg/mL) at 17 but not 43 weeks compared with candesartan (0.7+/-7.8 pg/mL) or enalapril (-0.8+/-11. 3 pg/mL). Brain natriuretic peptide decreased with combination therapy (5.8+/-2.7 pmol/L; P<0.01) compared with candesartan (4. 4+/-3.8 pmol/L) and enalapril alone (4.0+/-5.0 pmol/L).
Candesartan alone was as effective, safe, and tolerable as enalapril. The combination of candesartan and enalapril was more beneficial for preventing left ventricular remodeling than either candesartan or enalapril alone.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study is a trial of combination neurohormonal blockade using an angiotensin II antagonist (candesartan), an angiotensin-converting enzyme inhibitor (enalapril) and a beta-blocker (metoprolol) in patients with congestive heart failure (CHF). OBJECTIVES: Primary objectives of stage I are to determine the efficacy (via the 6 min walk test) and safety of candesartan alone, and in combination with enalapril, versus enalapril alone. Secondary objectives are to determine the effect of the above combinations on neurohormones, ventricular function, quality of life and symptoms. Stage II objectives are similar, evaluating the effect of the addition of metoprolol or placebo to the above medication(s). DESIGN: Randomized, two-stage trial consisting of a three-way comparison (stage I), followed by a 3 x 2 partial factorial design (stage II). SETTING: Sixty out-patient clinics in five countries. PATIENTS: Patients with symptoms of CHF (New York Heart Association functional classes II to IV), ejection fraction less than 40% and 6 min walk distance of 500 m or less. INTERVENTIONS: In stage I, 770 patients are randomized to receive candesartan alone, enalapril alone, or candesartan plus enalapril. After five months (end of stage I), patients are assessed for eligibility to be randomized in stage II. Those who are not candidates for randomization to beta-blocker or placebo are followed on their stage I medications until the end of the study. In stage II, patients are randomized to receive metoprolol or placebo for a further six months in addition to their stage I medications. Endpoints are measured at baseline, end of stage I (week 20) and end of stage II (week 46). STUDY STATUS: The study has recently completed follow-up in both stages. The findings from this study will be used to design a large scale mortality study that will help further define the role of neurohormonal blockade in patients with CHF.
The Canadian journal of cardiology 01/1998; 13(12):1166-74. · 3.12 Impact Factor