Steven E.S. Miner

Clinical chemistry and molecular biology of homocysteine metabolism: an update.

OBJECTIVE To summarize recent developments in our understanding of homocysteine as a clinically relevant and independent predictor of vaso-occlusive disease (including atherosclerosis and thromboembolism), as an early indicator of folate or cobalamin deficiency, and as a key factor in the pathogenesis of neural tube defects. METHODS AND RESULTS To determine total homocysteine, plasma or serum must be separated shortly after collection and subjected to chemical reduction. Reference intervals should take into account the prevalence of physiological hyperhomocystinemia. A common cause of hyperhomocystinemia is a genetic predisposition caused by a polymorphic substitution in the methylenetetrahydrofolate reductase (MTHFR) gene, which can be readily detected by molecular means. CONCLUSION Determination of homocysteine and MTHFR testing should be limited to laboratories with relevant expertise and ability to maintain the high degree of precision required for reliable interpretation. Assays should be offered in selected cases with clinical features or laboratory findings suggestive of hyperhomocystinemia, since treatment is simple and may be highly effective.

Comparison of bivalirudin versus heparin on radial artery occlusion after transradial catheterization.

Background: Anticoagulant therapy is required to prevent radial artery occlusion (RAO) after transradial catheterization. There is no data comparing bivalirudin to standard heparin. Methods: We studied 400 consecutive patients. In case of diagnostic angiography‐only (n = 200), they received an intravenous bolus of heparin (70 U kg−1) immediately before sheath removal whereas in case of angiography followed by ad hoc percutaneous coronary intervention (n = 200), they received bivalirudin (bolus 0.75 mg kg−1, followed by infusion at 1.75 mg/kg/h). RAO was assessed 4–8 weeks later using two‐dimensional echography‐doppler and reverse Allens test with pulse oximetry. Results: At follow‐up, 21 of the 400 (5.3%) patients were found to have RAO with no significant difference between the two groups (3.5% bivalirudin vs. 7.0% heparin, P = 0.18). Patients with RAO had a significantly lower weight compared to patients without RAO (78 ± 13 kg vs. 86 ± 18 kg, P = 0.011). By multivariate analysis, a weight <84 kg (OR: 2.78, 95% CI 1.08–8.00, P = 0.032) and a procedure duration ≤20 min (OR: 7.52, 95% CI 1.57–36.0, P = 0.011) remained strong independent predictors of RAO. All cases of radial occlusion were asymptomatic and without clinical sequelae. Conclusion: Delayed administration of bivalirudin or heparin for transradial catheterization provides similar efficacy in preventing RAO. Because of its low cost, a single bolus of heparin can be preferred in case of diagnostic angiography whereas bivalirudin can be contemplated in case of ad hoc percutaneous coronary intervention.

Pyridoxine improves endothelial function in cardiac transplant recipients

BACKGROUND Endothelial dysfunction is common in cardiac transplant recipients and predicts the development of transplant coronary artery disease. Hyperhomocysteinemia is associated with endothelial dysfunction in the general population, is common in transplant recipients, and has been associated with transplant coronary artery disease. Thus therapy that decreases homocysteine concentrations might also improve endothelial function and decrease the risk of transplant coronary artery disease. Folate and pyridoxine are important cofactors in distinct aspects of homocysteine metabolism. The purpose of this study was to determine whether folate or pyridoxine supplementation improves endothelial function in cardiac transplant recipients. METHODS AND RESULTS This was a double-blind, randomized, placebo-controlled trial. We assigned 31 transplant recipients to either pyridoxine (n = 11:100 mg/day), folate (n = 12:5 mg/day), or placebo (n = 8) for 10 weeks. Fasting and post-methionine-load (methionine 100 mg/kg orally) homocysteine concentrations were determined. Brachial artery flow-mediated dilatation was used as a measure of endothelial function. At follow-up, we noted no significant changes in homocysteine concentrations in any of the groups. However, pyridoxine supplementation was associated with a significant improvement in endothelial function (2.8 +/- 6.7 to 6.9 +/- 6.3, p = 0.05). No significant changes were seen in patients treated with folate or placebo. CONCLUSIONS Pyridoxine, but not folate supplementation, significantly improves endothelial function in cardiac transplant recipients.

The sPLA2 Inhibition to Decrease Enzyme Release After Percutaneous Coronary Intervention (SPIDER-PCI) Trial

Background— Secretory phospholipase A2 (sPLA2) may play a role in myonecrosis after elective percutaneous coronary intervention (PCI). Inhibition of this enzyme may have a beneficial effect. The central hypothesis of this study was that treatment with varespladib, a small-molecule inhibitor of sPLA2 would reduce postprocedural release of cardiac biomarkers after elective percutaneous coronary intervention. Methods and Results— Between October 2007 and June 2009, 144 stable patients were randomized in a phase II trial to receive varespladib 500 mg PO BID or placebo 3 to 5 days before and for 5 days after elective percutaneous coronary intervention. The primary end point was elevation of troponin I or creatine kinase-MB above the upper limit of normal at 6 to 8 or 18 to 24 hours after percutaneous coronary intervention. Mean age was 63±10 and 64±10 years, with 38% and 42% with diabetes mellitus and 29% and 28% with prior myocardial infarction for the varespladib and placebo groups, respectively. The primary end point occurred in 75% of varespladib and 63% of placebo patients (P=0.14). Troponin I 3 times the upper limit of normal was observed in 57% and 50% (P=0.39) and creatine kinase-MB 2 times the upper limit of normal in 14% and 3% (P=0.018). Median (first and third quartiles) change in high-sensitivity C-reactive protein in these 2 groups was 0.65 mg/L (−0.18 and 1.48) and 0.70 mg/L (0.00 and 1.50) at 18 to 24 hours (P=0.81) and 0.20 mg/L (−0.70 and 1.40) and 0.60 mg/L (−0.12 and 1.72) at 3 to 5 days (P=0.23), whereas change in sPLA2 activity at 3 to 5 days in a subset was −2.85 ng/ml (−3.40 and −1.85) and 0.25 ng/ml (−0.20 and 0.85) (P<0.001). Conclusions— Inhibition of sPLA2 by varespladib administered for 3 to 5 days before the procedure does not reduce periprocedural myonecrosis associated with elective percutaneous coronary intervention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00533039.

Outcomes of prenatally diagnosed tetralogy of Fallot: Implications for valve-sparing repair versus transannular patch

OBJECTIVES To assess outcomes of prenatally diagnosed tetralogy of Fallot and determine factors associated with the choice to undergo a valvesparing repair versus transannular patch, and the use of prostaglandins at birth. METHODS All cases at The Hospital for Sick Children (Toronto, Ontario) with a fetal diagnosis of tetralogy of Fallot from 1998 to 2006, were reviewed for demographic and fetal echocardiographic data to determine factors associated with the valve-sparing repair and need for perinatal support. RESULTS Sixty-four fetuses met inclusion criteria (median gestational age 22 weeks) with 47 live births. Twenty-six underwent valve-sparing repair (median age 5.7 months) and 14 underwent transannular patch repair (median age 4.5 months). There were seven deaths before surgery and one post-transannular patch repair. One patient required a transannular patch repair after the initial valve-sparing repair. Twelve of 29 (41%) patients received prostaglandins at birth. Type of surgical repair, use of prostaglandins and postnatal death were among the outcomes investigated. The mean pulmonary valve (PV) z-score was -3.0+/-2.0 and the mean PV/aortic valve (AoV) ratio was 0.65+/-0.10. Lower PV z-score (P=0.04), smaller PV/AoV ratio (P=0.04) and the presence of nonantegrade arterial duct flow (P=0.02) were associated with prostaglandin use. A higher PV/AoV ratio was associated with valvesparing repair (P=0.04). Fetal z-scores of the PV, AoV and right pulmonary artery at 29 to 32 weeks gestational age correlated with respective postnatal z-scores (P=0.01). CONCLUSION Fetal echocardiographic variables were associated with the use of prostaglandins and valve-sparing repair in fetuses with tetralogy of Fallot, and at 29 weeks, correlated with postnatal valve diameters.

Prehospital diagnosis and triage of ST-elevation myocardial infarction by paramedics without advanced care training

BACKGROUND Prehospital triage of ST-elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (PCI) reduces treatment times. Prehospital triage and transport of STEMI patients have traditionally been undertaken in emergency medical service systems with Advanced Care Paramedics (ACPs). However, ACPs are not available in many regions. A pilot study was conducted to determine the feasibility of prehospital STEMI triage in a region with only Primary Care Paramedics. METHODS Hemodynamically stable patients with chest pain and suspected STEMI were brought directly to a catheterization laboratory for primary PCI. End points included accuracy of prehospital STEMI identification, complications during transfer, and treatment times. RESULTS One hundred thirty-four consecutive patients with suspected STEMI were triaged for primary PCI. Only 1 patient developed complications during transport (rapid atrial flutter) that required ACP skills. One hundred thirty-three patients underwent urgent angiography, and 105 patients underwent PCI. Based on physician interpretation of the prehospital electrocardiogram, there was agreement with triage decision for 121 (90%) of the 134 cases. The final diagnosis based on the angiogram and cardiac markers was true STEMI for 106 patients and false positive for 28 patients. The median first medical contact to balloon time was 91 (81-115) minutes. CONCLUSIONS Hemodynamically stable patients with suspected STEMI can be safely and effectively transported directly for primary PCI by paramedics without advanced care training. Prehospital STEMI triage for primary PCI can be extended to regions that have few or no paramedics with advanced care training.

Hyperhomocysteinemia and transplant coronary artery disease in cardiac transplant recipients

Background: In cardiac transplant recipients, long‐term survival may be limited by transplant coronary artery disease (TxCAD). Hyperhomocysteinemia (Hhcy) has been associated with vascular disease and is common in transplant recipients. The objective of this study was to determine the relationship between fasting homocysteine (Hcy) concentrations and TxCAD in a cohort of cardiac transplant recipients. 
Methods: Forty‐eight patients more than 5 yr after transplant were recruited from a cohort of 72 consecutive patients with in‐depth analysis of homocysteine levels from the Cardiac Transplant Clinic. Early morning fasting blood was obtained, and the plasma separated and frozen within 30 min. Hcy concentrations were determined by high‐performance liquid chromatography (HPLC) with pulsed integrated amperometry. Coronary angiograms were reviewed in a blinded fashion. TxCAD was diagnosed, using the most recent angiogram, when a >25% lesion was present anywhere in the coronary tree. 
Results: Forty‐eight patients transplanted between 1985 and 1994 were studied. The mean Hcy concentration for the cohort was 23.5±5.0 μmol/L, all patients had homocysteine levels above the upper range of normal (5–15 μmol/L). Hcy concentrations were significantly higher in patients with angiographic evidence of TxCAD: 25.0±5.9 vs. 21.9±3.4 μmol/L, p=0.03. This effect persisted when covariates were taken into account using logistic regression analysis. 
Conclusions: Hhcy is associated with TxCAD. Prospective studies are required to confirm this association and to assess the efficacy of Hcy‐lowering therapy in this patient population.

Effects of folic acid fortification and multivitamin therapy on homocysteine and vitamin B12 status in cardiac transplant recipients

Abstract Background Hyperhomocysteinemia is a frequent finding after cardiac transplantation, but increased folate intake induces a decrease in total homocysteine concentrations. In 1998, food in Canada was fortified nationwide with folic acid. We assessed the impact of routine folate fortification on homocysteine concentrations in our cardiac transplant population. Methods In 18 subjects, we measured total homocysteine (tHcy), serum folate, and cobalamin concentrations in 1997 (before folate fortification) and in 1998 (after fortification). We repeated the analysis after specific multivitamin supplementation for 10 weeks. Results We found a significant decrease in baseline tHcy concentrations and in folate concentrations between 1997 and 1998. However, we also found a decrease in serum cobalamin concentrations. We found a correlation between decreased cobalamin concentrations and the methionine synthase A2756G genotype, but not with other common polymorphisms associated with homocysteine metabolism. After multivitamin supplementation, we observed a trend toward further decrease in tHcy concentrations and a significant increase in serum folate and cobalamin concentrations. Finally, we measured serum methylmalonic acid concentrations, an index of tissue cobalamin status. We did not find a correlation between increased methylmalonic acid concentrations and decreased serum cobalamin, perhaps related to the confounding effect of altered renal status on methylmalonic acid excretion. Conclusions National folate fortification was associated with decreased tHcy and increased folate concentrations in our cardiac transplant population. Additional administration of vitamin supplements induced a further decrease in tHcy and an increase in folate. Finally, folate fortification unveiled cobalamin deficiency in some patients, associated with the methionine synthase A2756G mutation.

Symptoms of disturbed sleep predict major adverse cardiac events after percutaneous coronary intervention.

BACKGROUND Disturbed sleep is associated with atherosclerosis in native coronary arteries and may be associated with adverse cardiac events after percutaneous coronary intervention (PCI). We sought to determine the association between symptoms of disturbed sleep and adverse cardiovascular events after PCI. METHODS Outpatients who were stable after successful PCI were assessed for symptoms of disturbed sleep with 10 true/false questions. Follow-up was performed at least 4 years after PCI. The primary outcome was a composite of death, myocardial infarction (MI), and repeated revascularization. RESULTS Three hundred eighty-eight patients (mean age, 66 ± 11 years) reported on average 3.1 ± 2.1 sleep disturbance symptoms. Follow-up was performed on average 4.4 years after the incident PCI. The primary outcome occurred in 25% of patients. An association was seen between the number of sleep disturbance symptoms and the occurrence of the primary end point. Patients with zero symptoms had a 4-year event rate of 12% compared with a 67% event rate for those with 9 symptoms. On multivariable analysis, sleep symptoms, diabetes mellitus, and the number of diseased coronary vessels were independently associated with the primary end point. Each additional sleep symptom was associated with a hazard ratio (HR) of 1.2 (P = 0.001). The results were driven primarily by the association between symptoms of disturbed sleep and the need for repeated revascularization (repeated PCI HR, 1.9; P = 0.003; coronary artery bypass grafting (CABG) HR, 1.5; P = 0.001). CONCLUSIONS Symptoms of disturbed sleep were associated with increased risk of long-term adverse cardiovascular outcomes after successful PCI.

Obesity Cardiovascular Disease and the Failure of Public Health Education.

The authors of the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study [(1)][1] deserve congratulations for their impressive work. The paper covers a lot of ground, but perhaps the most important finding is the notably high prevalence of obesity, particularly in