Low intracellular magnesium levels promote platelet-dependent thrombosis in patients with coronary artery disease.

BACKGROUND: Although reduced intracellular levels of magnesium have been described in patients with acute myocardial infarction, its significance as a regulator of thrombosis remains unknown. METHODS AND RESULTS: To determine whether reduced intracellular levels of magnesium enhance platelet-dependent thrombosis, we evaluated 42 patients with coronary artery disease (CAD) by exposing porcine aortic media to their flowing unanticoagulated venous blood for 5 minutes by using an ex vivo perfusion (Badimon) chamber. Baseline analysis demonstrated significant associations between intracellular levels of magnesium, platelet-dependent thrombosis (P =.02), and platelet P-selectin (CD62P) expression (P <.05). Patients were divided into 2 groups: below (n = 22) and above (n = 20) the median intracellular levels of magnesium (1.12 microg/mg protein). There were no significant differences in age, body mass index, serum lipids, fibrinogen, platelet count, or serum magnesium levels between the two groups. Platelet-dependent thrombosis was significantly higher in patients with intracellular levels of magnesium below compared with above median (150 +/- 128 vs 45 +/- 28 microm(2)/mm, P <.004). Neither platelet aggregation nor CD62P expression was significantly different between the two groups. CONCLUSIONS: Platelet-dependent thrombosis was significantly increased in patients with stable CAD with low intracellular levels of magnesium, suggesting a potential role for magnesium supplementation in CAD.

Exercise conditioning and heart rate variability: evidence of a threshold effect.

BACKGROUND: A protective effect of exercise in preventing sudden cardiac death is supported by studies in healthy populations as well as in patients with cardiac disease. The mechanisms involved in this protective effect are unknown. HYPOTHESIS: We hypothesized that exercise conditioning would beneficially alter autonomic nervous system tone, measured by heart rate variability. METHODS: We prospectively studied 20 cardiac patients enrolled in a Phase 2 12-week cardiac rehabilitation program following a recent cardiac event. The patients underwent 24 h Holter monitoring at program entry and 12 weeks later. Heart rate variability analysis was assessed for both time domain and spectral analysis. RESULTS: The group demonstrated a modest mean conditioning effect, indicated by an average reduction in resting heart rate from 81 +/- 16 to 75 +/- 12 beats/min (p = 0.03), and an increase in training METS from 2.1 +/- 0.4 to 3.3 +/- 1.1 (p < 0.0001). Overall, 15 of 20 (75%) patients demonstrated increased total and high-frequency power, and mean high-frequency power was significantly increased (3.9 +/- 1.4 vs. 4.4 +/- 1.0 ln, p = 0.05). When stratified according to the magnitude of exercise conditioning, patients achieving an increase of > 1.5 training METS demonstrated significant increases in SDNN, SDANN index, SDNN index, pNN50, total power, and high-frequency power (all p < 0.05) (see text for explanation of abbreviations). CONCLUSIONS: Exercise conditioning improves heart rate variability in cardiac patients, particularly in patients who achieve a threshold of > 1.5 training METS increase over a 12-week period. These study results are supportive of the concept that exercise training lowers the risk of sudden cardiac death via increased vagal tone, which likely beneficially alters ventricular fibrillatory and ischemic thresholds.

Blood glucose and platelet-dependent thrombosis in patients with coronary artery disease.

OBJECTIVES: To investigate the influence of blood glucose on platelet-dependent thrombosis (PDT). BACKGROUND: Elevated blood glucose is a predictor of adverse cardiovascular risk independent of a diagnosis of diabetes, possibly due to adverse effects promoting thrombosis. The effects of blood glucose on PDT have not been characterized. METHODS: An ex vivo extracorporeal perfusion protocol was used to measure PDT in 42 patients with stable coronary artery disease (CAD). The Badimon chamber was perfused with unanticoagulated venous blood and PDT evaluated using computerized morphometry. Whole blood impedance aggregometry and flow cytometry evaluated platelet aggregation and P-selectin expression, respectively. RESULTS: Using a multivariate stepwise regression model, blood glucose was the best independent predictor of PDT (R2 = 0.19, p < 0.008), followed by apolipoprotein B (R2 = 0.18, p = 0.002) and intracellular magnesium levels (R2 = 0.12, p = 0.02). Platelet-dependent thrombosis was significantly greater in patients with blood glucose >, compared with <, the median value of 4.9 mmol/l (159 +/- 141 vs. 67 +/- 69 microm2/mm, p < 0.01). Neither platelet aggregation nor P-selectin expression was significantly different between the two groups. Insulin levels correlated with blood glucose (r = 0.56, p = 0.0003), but were not independently associated with either PDT, platelet aggregation or P-selectin expression. A two-way analysis of variance demonstrated an interaction between insulin (>126 pmol/l) and blood glucose (>4.9 mmol/l) in modulating PDT (F [1,38] = 8.5, p < 0.006). CONCLUSIONS: Blood glucose is an independent predictor of PDT in stable CAD patients. The relationship is evident even in the range of blood glucose levels considered normal, indicating that the risk associated with blood glucose may be continuous and graded. These findings suggest that the increased CAD risk associated with elevated blood glucose may be, in part, related to enhanced platelet-mediated thrombogenesis.

Beneficial antithrombotic effects of the association of pharmacological oral magnesium therapy with aspirin in coronary heart disease patients.

The use of magnesium in the treatment of acute myocardial infarction remains controversial despite preliminary experimental evidence that magnesium plays a beneficial role as a regulator of thrombosis. The aim of our study was to determine whether oral magnesium treatment inhibits platelet-dependent thrombosis (PDT) in stable patients with coronary artery disease (CAD). In a randomized prospective, double-blind, cross-over and placebo controlled study, 42 patients with stable CAD (37 men, 5 women, mean age 68 +/- 9 years) on aspirin received either magnesium oxide tablets (800-1,200 mg/day) or placebo for 3 months (Phase 1) followed by a 4-week washout period, and the cross-over treatment for 3 months (Phase 2). PDT, platelet aggregation, platelet P-selectin flow-cytometry, monocyte tissue factor procoagulant activity (TF-PCA) and adhesion molecules density were assessed before and after each phase. PDT was evaluated by an ex-vivo perfusion model using the Badimon chamber. Median PDT was significantly reduced by 35 percent in patients who received magnesium versus placebo (D change from baseline: -24 vs. 26 microm2/mm; p = 0.02, respectively). There was no significant effect of magnesium treatment on platelet aggregation, P-selectin expression, monocyte TF-PCA or adhesion molecules. Oral magnesium treatment inhibits PDT in patients with stable CAD. This effect appears to be independent of platelet aggregation or P-selectin expression, and is evident despite aspirin therapy. These findings suggest a potential mechanism whereby magnesium may beneficially alter outcomes in patients with CAD.

Oral magnesium supplementation inhibits platelet-dependent thrombosis in patients with coronary artery disease.

The use of magnesium in the treatment of acute myocardial infarction remains controversial despite preliminary experimental evidence that magnesium plays a beneficial role as a regulator of thrombosis. This study examines whether oral magnesium treatment inhibits platelet-dependent thrombosis (PDT) in patients with coronary artery disease (CAD). In a randomized prospective, double-blind, crossover, and placebo-controlled study, 42 patients with CAD (37 men, 5 women, mean age 68 +/- 9 years) on aspirin received either magnesium oxide tablets (800 to 1,200 mg/day) or placebo for 3 months (phase 1) followed by a 4-week wash-out period, and the crossover treatment for 3 months (phase 2). PDT, platelet aggregation, platelet P-selectin flow cytometry, monocyte tissue factor procoagulant activity (TF-PCA), and adhesion molecule density were assessed before and after each phase. PDT was evaluated by an ex vivo perfusion model using the Badimon chamber. Median PDT was significantly reduced by 35% in patients who received magnesium versus placebo (delta change from baseline -24 vs 26 mm2/mm; p = 0.02, respectively). There was no significant effect of magnesium treatment on platelet aggregation, P-selectin expression, monocyte TF-PCA, or adhesion molecules. Oral magnesium treatment inhibited PDT in patients with stable CAD. This effect appears to be independent of platelet aggregation or P-selectin expression, and is evident despite aspirin therapy. These findings suggest a potential mechanism whereby magnesium may beneficially alter outcomes in patients with CAD.

Risk stratification for exercise training in cardiac patients: do the proposed guidelines work?

PURPOSE: Four authoritative organizations (American Association of Cardiovascular and Pulmonary Rehabilitation [AACVPR], the American College of Cardiology [ACC], the American College of Physicians [ACP], and the American Heart Association [AHA]) have risk stratification guidelines for supervised exercise in patients with cardiovascular disease. The ability of the guidelines to predict exercise complications is untested. METHODS: A prospective sample was evaluated that included 239 patients enrolled for a total of 5720 patient exercise hours in a phase II supervised outpatient cardiac rehabilitation exercise program between December 1, 1992, and June 16, 1995, who had had preprogram stress testing and/or left ventricular ejection fraction determination. Complications during supervised exercise were measured. RESULTS: Overall, 12 patients experienced complications during supervised exercise. None of the guidelines was predictive of complications (positive predictive values, 3-7%). Regression analyses demonstrated that current cigarette smoking was the only predictor of complications. There was reasonable correlation of patient risk stratification among the four guidelines (r = 0.19-0.47; P < 0.0001). CONCLUSIONS: Currently proposed exercise risk stratification guidelines are not predictive of complications during supervised exercise. Further work is needed before exercise risk stratification guidelines are used to adjudicate use of supervised services.

Association of IL-6 gene alleles with systemic lupus erythematosus (SLE) and with elevated IL-6 expression.

To evaluate the association of alleles of regions having regulatory potential in the IL-6 gene, with SLE, the AT-rich minisatellite in the 3' flanking region and the 5' promoter-enhancer of the IL-6 gene were genotyped by PCR- and RFLP-based methods. The AT-rich minisatellite allele distribution pattern was significantly different in SLE (n = 146) as compared to 139 controls (chi 2(7) = 48.97, P = 0.001, Caucasians; and chi 2(7) = 19.93, P = 0.006, African-Americans). In either race, short allele sizes (< or = 792 bp) were seen exclusively in SLE patients (P = 0.001), whereas the 828-bp allele was over-represented in controls (P = 0.015 and 0.002). In contrast, there was no preferential association of SLE with G/C alleles in the 5' region of the IL-6 gene. Furthermore, our results suggest that the 3' minisatellite alleles have biological significance: (1) B lymphoblastoid cells of patients having one or two SLE-associated alleles secreted IL-6 in 3- to 4-fold higher levels than non-allelic cells (P < 0.05); (2) higher percentages (approximately 4-fold) of IL-6 positive monocytes were observed in individuals having SLE-associated IL-6 alleles; (3) in lupus patients having SLE-associated minisatellite alleles, IL-6 mRNA stability was significantly enhanced.

Plasma apolipoprotein B levels predict platelet-dependent thrombosis in patients with coronary artery disease.

Elevated plasma apolipoprotein B is a known risk factor for atherosclerotic coronary artery disease (CAD), however its relationship to arterial thrombosis is unexplored. We prospectively assessed apolipoprotein B and platelet-dependent thrombosis (PDT) in 42 CAD patients (37 men, 5 women, mean age 68 +/- 9 years), by exposing porcine aortic media to their flowing unanticoagulated venous blood for 5 min using an ex vivo perfusion (Badimon) chamber. PDT was significantly correlated with apolipoprotein B (r = 0.41, p = 0.009), intracellular magnesium levels (r = -0.46, p = 0.003) fasting blood glucose (r = 0.47, p = 0.002), and total cholesterol (r = 0.43, p = 0.006). PDT did not correlate with serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein A-I or fibrinogen levels. These findings suggest that the positive relationship of elevated apolipoprotein B to CAD may be, in part, related to its prothrombotic effects.

Intracellular magnesium predicts functional capacity in patients with coronary artery disease.

To determine whether increased intracellular levels of magnesium ([Mg]i) are associated with enhanced functional capacity, we performed symptom-limited exercise treadmill testing on 42 stable coronary artery disease (CAD) patients (37 men, 5 women, mean age 68 +/- 9 years). [Mg]i was found to be an independent and significant predictor of exercise duration (R = 0.31, p = 0.02) in a multivariate stepwise regression model. Patients with > normal [Mg]i of 1.23 microg/mg protein (n = 13) had a significantly greater mean functional capacity, measured in higher achieved metabolic equivalents (10.6 +/- 2.5 vs. 8.9 +/- 2.3, p < 0.05) and exercise duration (9.4 +/- 2.3 vs. 7.9 +/- 2.2 min, p < 0.05) compared to patients with [Mg]i

Heart rate variability reproducibility and stability using commercially available equipment in coronary artery disease with daily life myocardial ischemia.

Heart rate variability (HRV) appears to be a strong predictor of death. The reproducibility of HRV measurements in patients with stable coronary artery disease (CAD) who have daily life myocardial ischemia, however, is unknown. Thirty patients with stable CAD (25 men and 5 women; aged 62 +/- 8 years) with daily life ischemia were studied with 2 consecutive 24-hour Holter monitoring recordings. Intra- and interobserver reproducibility of the HRV measures was high, with correlations ranging from 0.990 to 0.999 (p < 0.0001). Strong correlations between time and frequency domain HRV measures were observed (range 0.912 to 0.963; p < 0.0001). Both the frequency and duration of ischemia, measured by ST change, varied significantly by day for each patient (s = 155.5; p < 0.0001; s = 232.5, p < 0.0001, respectively). Correlations for HRV measurements between days remained high (range 0.871 to 0.983; p < 0.0001), despite stratification by magnitude of daily ischemia. Thus, 24-hour HRV measurements are stable in CAD patients with daily life myocardial ischemia over a short period, despite varying magnitudes of daily ischemia. These results support the use of HRV as a clinical tool and an outcome measure in future CAD intervention studies using commercially available equipment.

Safety of medically supervised exercise in a cardiac rehabilitation center.

Medically supervised exercise continues to have a low major cardiovascular complication rate. Direct gym supervision by a physician does not appear necessary for safety. The currently proposed cardiac rehabilitation risk stratification criteria do not appear to identify patients at risk for these major complications. The safety of exercise programs with less supervision and electrocardiographic telemetry monitoring is unknown.