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OBJECTIVE--Recent observations indicate that the delivery of nitric oxide by endothelial nitric oxide synthase (eNOS) is not only critical for metabolic homeostasis, but could also be important for mitochondrial biogenesis, [...]

Nitric oxide (NO) plays a major role in the regulation of cardiovascular and metabolic homeostasis, as evidenced by insulin resistance and arterial hypertension in endothelial NO synthase (eNOS) null mice. Extrapolation of these findings to humans is difficult, however, because eNOS gene deficiency has not been reported. eNOS gene polymorphism and impaired NO synthesis, however, have been reported in several cardiovascular disease states and could predispose to insulin resistance. High-fat diet induces insulin resistance and arterial hypertension in normal mice. To test whether partial eNOS deficiency facilitates the development of insulin resistance and arterial hypertension during metabolic stress, we examined effects of an 8-week high-fat diet on insulin sensitivity (euglycemic clamp) and arterial pressure in eNO[S.sup.+/-] mice. When fed a normal diet, these mice had normal insulin sensitivity and were normotensive. When fed a high-fat diet, however, eNO[S.sup.+/-] mice developed exaggerated arterial hypertension and had fasting hyperinsulinemia and a 35% lower insulin-stimulated glucose utilization than control mice. The partial deletion of the eNOS gene does not alter insulin sensitivity or blood pressure in mice. When challenged with nutritional stress, however, partial eNOS deficiency facilitates the development of insulin resistance and arterial hypertension, providing further evidence for the importance of this gene in linking metabolic and cardiovascular disease., Metabolic insulin resistance is a problem of utmost clinical importance and a major risk factor for cardiovascular morbidity and mortality. Epidemiological studies indicate that insulin resistance and arterial hypertension are [...]

Background: Administration of 13-cis retinoic acid (isotretinoin) for acne is occasionally accompanied by hyperlipidemia. It is not known why some persons develop this side effect. Objective: To determine whether isotretinoin triggers a familial susceptibility to hyperlipidemia and the metabolic syndrome. Design: Cross-sectional comparison. Setting: University hospital in Lausanne, Switzerland. Participants: 102 persons in whom triglyceride levels increased at least 1.0 mmol/L (>=89 mg/dL) (hyperresponders) and 100 persons in whom triglyceride levels changed 0.1 mmol/L ( Measurements: Waist-to-hip ratio; fasting glucose, insulin, and lipid levels; and apoE genotype. Results: Hyperresponders and nonresponders had similar pretreatment body weight and plasma lipid levels. When reevaluated approximately 4 years after completion of isotretinoin therapy, hyperresponders were more likely to have hypertriglyceridemia (triglyceride level >2.0 mmol/L [177 mg/dL]; odds ratio [OR], 4.8 [95% CI, 1.6 to 13.8]), hypercholesterolemia (cholesterol level >6.5 mmol/L [>252 mg/dL]; OR, 9.1 [CI, 1.9 to 43]), truncal obesity (waist-to-hip ratio >0.90 [OR, 11.0 (CI, 2.0 to 59]), and hyperinsulinemia (insulin-glucose ratio >7.2; OR, 3.0 [CI, 1.6 to 5.7]). In addition, more hyperrespondes had at least one parent with hypertriglyceridemia (OR, 2.6 [CI, 1.2 to 5.7]) or a ratio of total to high-density lipoprotein cholesterol that exceeded 4.0 (OR, 3.5 [CI, 1.5 to 8.0]). Lipid response to isotretinoin was closely associated with the apoE gene. Conclusion: Persons who develop hypertriglyceridemia during isotretinoin therapy for acne, as well as their parents, are at increased risk for future hyperlipidemia and the metabolic syndrome.

Impaired glucose tolerance (IGT) is characterized by insulin resistance. Recently, defects in the insulin-signaling cascade have been implicated in the pathogenesis of insulin resistance. To study insulin signaling in IGT, [...]

Insulin-induced stimulation of blood flow and sympathetic nerve activity in skeletal muscle tissue is impaired in obesity, but the underlying mechanism is unknown. To determine whether insulin resistance alters sympathetic [...]

Little is known concerning the influence of remote prior coronary artery bypass grafting (CABG) on the outcome of patients with acute myocardial infarction (AMI). Therefore, this study evaluated 2,494 patients with AMI of whom 219 (8.8%) had a history of CABG a mean of 7.1 [+ or -] 3.7 years before the index AMI. Compared with all other patients, those with a history of CABG had an increased prevalence of a history of prior AMI (153 [70%] vs 547 [24%]), congestive heart failure (48 [22%] vs 236 [10%]), and angina pectoris (165 [75%] vs 787 [35%]), all p

Ideally, coronary angiography after myocardial infarction should be confined to patients at high risk for death or reinfarction as determined by clinical criteria and noninvasive testing. The percentage of patients undergoing the procedure is increasing; however, the greatest increase has been in low- and medium-risk patients.

Heart attacks (myocardial infarctions) that damage the anterior wall of the heart muscle (myocardium) are usually more serious than those that affect the inferior wall. However, some patients with inferior myocardial damage may benefit from aggressive treatment, including clot-dissolving drugs (thrombolytics). Atrioventricular block or intraventricular block (abnormality of the electrical impulse that paces the heart) identifies patients who are likely to die before leaving the hospital, although it does not predict greater long-term mortality. Bundle branch block (BBB; a type of electrical conduction abnormality) may also indicate higher mortality. A total of 1,634 patients with inferior Q-wave (a measurement on the electrocardiogram) heart attacks were examined, and the degree of block (conduction abnormality) was determined. Patients with right BBB after a heart attack were more likely to die during the first year after discharge from the hospital. Generally, these patients were older, and had a history of heart failure and previous heart attack. Surprisingly, there was no difference in the incidence of atrioventricular block between patients with BBB and those without it, although this could have been the result of a small sample. Patients with inferior myocardial infarction complicated by right BBB are at higher risk of dying, and may benefit from aggressive approaches, including angiography (widening the diameters of coronary arteries). (Consumer Summary produced by Reliance Medical Information, Inc.)

Drugs categorized as class 1C antiarrhythmic agents, specifically encainide and flecainide, are used to treat patients with ventricular arrhythmias, or irregular rhythms of the ventricles of the heart. These drugs work by depressing the conduction velocity of the myocardium (heart muscle) but are known to cause ventricular proarrhythmic effects that aggravate arrhythmia. Their ability to produce arrhythmias in the atrium in addition to the ventricle is not clear. Computerized hospital pharmacy records were examined to discover all patients in whom flecainide or encainide were prescribed and administered. Six of 60 patients who received one of these class 1C drugs experienced new or modified atrial arrhythmias and details of these cases are described to illustrate the abnormalities seen on electrocardiogram. The atrial arrhythmias caused symptoms in all six patients and were potentially life-threatening in two of them. Following drug withdrawal the arrhythmias resolved and did not reappear during long-term follow-up. These two drugs have the potential to cause serious or life-threatening proarrhythmic effects when used to treat atrial or ventricular arrhythmias. (Consumer Summary produced by Reliance Medical Information, Inc.)

Elevated heart rate (HR) during hospitalization and after discharge has been predictive of death in patients with acute myocardial infarction (AMI), but whether this association is primarily due to associated cardiac failure is unknown. The major purpose of this study was to characterize in 1,807 patients with AMI admitted into a multicenter study the relation of HR to in-hospital, after discharge and total mortality from day 2 to 1 year in patients with and without heart failure. HR was examined on admission at maximum level in the coronary care unit, and at hospital discharge. Both inhospital and postdischarge mortality increased with increasing admission HR, and total mortality (day 2 to 1 year) was 15% for patients with an admission HR between 50 and 60 beats/min, 41% for HR >90 beats/min and 48% for HR [greater than or equal to] 110 beats/min. Mortality from hospital discharge to 1 year was similarly related to maximal HR in the coronary care unit and to HR at discharge. in patients with severe heart failure (grade 3 or 4 pulmonary congestion on chest x-ray, or shock), cumulative mortality was high regardless of the level of admission HR (range 61 to 68%). However, in patients with pulmonary venous congestion of grade 2, cumulative mortality for patients with admission HR [greater than or equal to]90 beats/min was over twice as high as that in patients with admission HR (Am J Cardiol 1990;65:547-553), Elevated heart rate (HR) following heart attack (myocardial infarction, MI) has been thought to be related to dysfunction of the left ventricle, the major pump of the heart muscle, and is also thought to be predictive of subsequent death. The relationship between HR, mortality, and degree of heart failure was studied in 1,807 patients admitted to the hospital with MI. Patients with admission HR greater than 90 beats per minute (bpm) were slightly older, were more likely to have a history of risk factors (angina, congestive heart failure, and lung disease), were treated more often with digitalis and less often with beta-blockers, and had a higher incidence of arrhythmias (abnormal heart beat). Eighty percent of patients with HR less than 90 bpm had absent to mild heart failure (HF) and 5 to 7 percent had severe HF, while 58 percent of patients with HR over 90 bpm had absent to mild HF and 24 percent had severe HF. Total mortality (from day two to one year after admission) was 15 percent for patients with admission HR between 50 and 60 bpm, and increased to 41 percent at HR over 90 bpm and to 48 percent at HR over 110 bpm. Occurrence of fatal repeat MI was associated with HR over 90 bpm, but nonfatal repeat MI was not. Patients with severe heart failure did not differ on mortality rate based on HR, while mortality rates in patients with mild or moderate HF did increase with increasing HR. The study shows that HR during hospitalization is a significant and independent predictor of mortality following MI. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: Apolipoprotein(a) [apo(a)], the distinctive, highly polymorphic glycoprotein of lipoprotein(a), shares a series of common features with apolipoprotein E (apoE), which is implicated in the development of Alzheimer disease. Objective: To determine whether apo(a) is associated with Alzheimer disease. Design: Case-control study. Setting: University hospitals in Europe. Participants: 285 patients with Alzheimer disease and 296 controls. Measurements: Plasma lipoprotein(a) levels, size of the apo(a) isoforms, and apoE and apo(a) genotyping. Results: Among carriers of the apoE [element of] 4 allele, lipoprotein(a) was associated with a progressive, age-dependent increased risk for late-onset Alzheimer disease (odds ratio for patients [is greater than] 80 years of age, 6.0 [95% CI, 1.2 to 30.8]; P [is less than] 0.01). Among noncarriers older than 80 years of age, lipoprotein(a) was associated with a reduced risk for Alzheimer disease (odds ratio, 0.4 [CI, 0.2 to 0.9]; P [is less than] 0.05). Conclusions: In this convenience sample, lipaprotein(a) was an additional risk factor for late-onset Alzheimer disease in carriers of the apoE [element of] 4 allele. However, lipoprotein(a) may protect against late-onset Alzheimer disease in noncarriers., Apolipoprotein(a) seems to increase the risk of Alzheimer's disease in people who have apolipoprotein E epsilon4 but not in people who do not. In a study of 285 patients with Alzheimer disease and 296 healthy volunteers, apolipoprotein (a) caused a six-fold increased risk of Alzheimer's disease at the age of 80 in people with apoE epsilon4. In people who did not have apoE epsilon4, apolipoprotein (a) actually decreased the risk of Alzheimer's disease.

Interleukin-1 (IL-1) is cytotoxic to pancreatic [Beta]-cells, in part by activating several MAP kinases including the c-Jun N-terminal kinase (JNK). JNK in turn activates the transcription factor c-Jun which represses [...]

The Islet-Brain 1 (IB1) protein is a DNA-binding transactivator of the GLUT2 gene and the rat isoform of JIP-1, an inhibitor of the c-Jun N-terminal kinase (JNK). JNK is activated [...]

Macrophage Migration Inhibitory Factor (MIF) was shown to be a glucose-dependent islet-cell product that regulates insulin secretion in a positive manner[Proc Natl Acad Sci USA, 1997 ;94:4782]. The characterization of [...]