The Triglyceride to HDL Ratio and Its Relationship to Insulin Resistance in Pre- and Postpubertal Children: Observation from the Wausau SCHOOL Project.

Insulin resistance (IR) is a risk factor for ischemic heart disease and diabetes and raises the triglyceride/high-density lipoprotein (TG/HDL) ratio in adults, but is not well defined in children. Purpose. To investigate the TG/HDL ratios in children as an IR marker. Methods. Wausau SCHOOL Project assessed 99 prepubertal and 118 postpubertal children. The TG/HDL ratio was correlated with numerous risk factors. Results. TG/HDL ratio was significantly correlated with QUICKI, HOMA-IR, zBMI, waist-to hip ratio, systolic and diastolic BP, LDL size and LDL number. A group of 32 IR children (HOMA-IR > 1 SD from the mean, i.e., >2.45) had significantly higher TG/HDL (3.11 ± 1.77) compared to non-IR children (1.86 ± 0.75). A TG/HDL ratio of ≥2.0 identified 32 of the 40 children deemed IR by HOMA-IR (>2.45) with a sensitivity of 0.80 and a specificity of 0.66. Children with TG/HDL ratio ≥3 were heavier and had higher BP, glucose, HOMA-IR, LDL number, and lower HDL level, QUICKI, and LDL size, regardless of pubertal status. Conclusion. The TG/HDL ratio is strongly associated with IR in children, and with higher BMI, waist hip ratio, BP, and more athrogenic lipid profile.

The use of ranolazine to facilitate electrical cardioversion in cardioversion-resistant patients: a case series.

BACKGROUND: Occasionally atrial fibrillation (AF) is resistant to electrical cardioversion (EC). Ranolazine (RZ) is an antianginal agent, which inhibits abnormal late Na(+) channel currents in cardiomyocytes and decreases Na(+) /Ca(++) overload. RZ is a potent inhibitor of after-depolarizations and triggered activity and prolongs atrial refractory periods. We postulated RZ could facilitate EC in patients resistant to EC. METHODS: Over a 3-year period, we identified 25 EC-resistant patients who had been administered oral RZ shortly after failing attempted EC. The anterior-posterior cardioversion approach was used and each patient had failed to be restored to sinus rhythm despite using up to the maximum output of a biphasic cardioversion device. Repeat EC was performed 3.5-4 hours after administration of 2 g of oral RZ using the same device, sedation, and lead placement. RESULTS: Sinus rhythm was successfully restored in 19 (76%) of 25 EC-resistant patients. Three patients spontaneously converted before the second attempt at EC within 4 hours of the RZ dose. Of the 22 patients undergoing another attempt at EC, 16 were successfully converted to sinus rhythm. Five of the six patients who were refractory to repeat EC despite RZ had AF of unknown duration and each is now in permanent AF. No adverse effects were noted. CONCLUSION: RZ shows promise as a safe and convenient agent to facilitate EC in EC-resistant patients. It appears to be most effective in patients whose AF duration is known to be less than 3 months.

Comparison of effectiveness and safety of ranolazine versus amiodarone for preventing atrial fibrillation after coronary artery bypass grafting.

Atrial fibrillation (AF) is common after coronary artery bypass grafting (CABG) and increases the morbidity and cost. Amiodarone reduces AF after CABG. Ranolazine, an antianginal agent, also prolongs atrial refractoriness and inhibits after depolarizations and triggered activity; effects that could decrease AF after CABG. The present study compared amiodarone versus ranolazine for the prevention of AF after CABG. A retrospective cohort study of patients undergoing CABG at Aspirus Hospital from June 2008 to April 2010. The patients received either amiodarone (400 mg preoperatively followed by 200 mg twice daily for 10 to 14 days) or ranolazine (1,500 mg preoperatively followed by 1,000 mg twice daily for 10 to 14 days). The primary end point was any identified AF after CABG. A total of 393 consecutive patients undergoing CABG (mean age 65 ± 10 years, 72% men) received either amiodarone (n = 211 [53.7%]) or ranolazine (n = 182 [46.3%]). AF occurred in 26.5% of the amiodarone-treated patients compared to 17.5% of the ranolazine-treated patient (p = 0.035). The univariate predictors of AF included amiodarone use, age, chronic lung disease, and congestive heart failure. The multivariate predictors of AF included amiodarone use (odds ratio 1.7, 95% confidence interval 1.01 to 2.91, p = 0.045 vs ranolazine), age (odds ratio 2.2 per 10 years, 95% confidence interval 1.63 to 2.95, p <0.001), and chronic lung disease (odds ratio 1.86, 95% confidence interval 1.00 to 3.43, p = 0.049). No difference was found in the risk of adverse events between the 2 therapies. In conclusion, ranolazine was independently associated with a significant reduction of AF compared to amiodarone after CABG, with no difference in the incidence of adverse events. Randomized studies should be conducted to confirm these results.

Suppression of frequent ventricular ectopy in a patient with hypertrophic heart disease with ranolazine: a case report.

BACKGROUND: Pro-arrhythmic concerns with most anti-arrhythmic agents in patients with significant left ventricular hypertrophy (LVH) limits options when anti-arrhythmic therapy is indicated. Ranolazine, an anti-anginal agent which inhibits late Na+ currents, indirectly causes a decrease in diastolic cardiomyocyte Ca++ levels producing an energy sparing effect. Ranolazine also inhibits triggered activity in animal studies and has anti-arrhythmic properties in patients with ischemic heart disease. Here we report the dramatic anti-arrhythmic effects of ranolazine in a patient with frequent ventricular and supraventricular ectopy in the setting of hypertrophic heart disease without significant coronary artery disease. METHODS: A 72 year old hypertensive patient with palpitations and significant exercise intolerance due to dyspnea was evaluated with echocardiography, thallium stress testing and cardiac catheterization. Holter monitor data prior to, and after institution of ranolazine 1000 mg twice daily was compared. Patient tolerance and sense of well being after ranolazine was assessed. RESULTS: Significant LVH was noted and obstructive coronary artery disease was ruled out by cardiac catheterization. Within two hours of the initial dose of ranolazine a marked decrease in ventricular ectopy was observed. Ventricular ectopy on Holter monitor decreased approximately 12 fold (23.8% of beats to1.9%) while supraventricular ectopy decreased approximately 7 fold (5.3% of beats to 0.8%). The decrease in ectopy was associated with an improved sense of well being. CONCLUSION: Ranolazine had rapid onset, potent anti-arrhythmic properties in the absence of obstructive coronary artery disease in a patient with LVH and may be an ideal agent in patients where few anti-arrhythmic options exist.

Electrophysiological Changes of the Atrium in Patients with Lone Paroxysmal Atrial Fibrillation.

BACKGROUND: The "Pill-in-Pocket" (PIP) is an approach to atrial fibrillation (AF) where oral anti-arrhythmics at 75% to 100% of the normal daily dose, given as a single dose, is used to convert recent-onset AF. Pro-arrhythmic risk has limited this approach to patients without structural heart disease (SHD). Ranolazine is an anti-anginal agent, which inhibits the abnormal late Na+ channel current resulting in decreased Na+/Ca++ overload. This inhibits after-depolarizations and reduces pulmonary vein firing, which have been implicated in the initiation and propagation of AF. Ranolazine increases atrial refractoriness and has no known pro-arrhythmic affects. Ranolazine is routinely given to patients with SHD. The ability of Ranolazine to terminate AF in man has not been described but if useful could be a safer PIP agent with application in the presence or absence of SHD. We describe our experience using oral Ranolazine to convert new or recurrent AF. METHOD: 2000 mg of ranolazine was administered to 35 patients with new (16 patients) or recurrent (19 patients) AF of at least 3 but not greater than 48 hours duration. Clinical features, echocardiographic data, and SHD were noted. Success was defined as restoring sinus rhythm within 6 hours of Ranolazine. RESULTS: All but 4 patients had some form of SHD. Twenty-five patients were in the hospital, 5 were in the office, and 5 were at home at the time Ranolazine was administered. Twenty-five of 35 patients converted to sinus rhythm. No pro-arrhythmic effects, hemodynamic instability, adverse rate effects, or perceived intolerance were noted. The 71% conversion rate was comparable to other reported PIP protocols and much higher than reported placebo conversion rates. CONCLUSIONS: High dose oral Ranolazine shows utility as a possible safe agent to convert new or recurrent AF. Larger placebo-controlled studies would appear to be warranted.

Suppression of non-sustained ventricular tachycardia with ranolazine: a case report.

BACKGROUND: Ranolazine is a new anti-anginal agent that inhibits abnormal late sodium currents, indirectly causing a decrease in diastolic cardiomyocyte calcium levels. This produces an energy-sparing effect and stabilizes cardiac membranes. Ranolazine has been shown to be a potent inhibitor of triggered activity in the experimental setting. METHODS: This case report describes the dramatic antiarrhythmic effects of ranolazine in a patient with highly symptomatic complex ventricular ectopy, including non-sustained ventricular tachycardia (NSVT). Cardiac ischemia and left ventricular systolic dysfunction were ruled out by cardiac catheterization. After failing standard treatment, we initiated ranolazine therapy. RESULTS: Ranolazine was effective in suppressing ectopic ventricular activity and completely suppressed NSVT. CONCLUSIONS: Further research on the anti-arrhythmic properties of ranolazine in the clinical setting is needed.

The use of oral ranolazine to convert new or paroxysmal atrial fibrillation: a review of experience with implications for possible "pill in the pocket" approach to atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia requiring treatment. High dose oral anti-arrhythmics may cardiovert some paroxysmal AF. This "pill in pocket" approach has allowed patients to treat themselves on an as needed basis. Pro-arrhythmic concerns have limited the usefulness of this approach to patients without structural heart disease. Ranolazine is an anti-anginal agent, which inhibits abnormal late Na+ channel currents in cardiomyocytes and decreases sodium-calcium overload. Ranolazine is a potent inhibitor of after-depolarizations, which have been implicated in the initiation and propagation of AF. Because ranolazine has no known pro-arrhythmic effects, it could be useful as a safe "pill in the pocket" agent if it were effective in converting AF. We describe our experience using oral ranolazine to convert new or paroxysmal AF. METHODS: 2000 mg of ranolazine were administered to 18 patients with new (11 patients) or paroxysmal (7 patients) AF of at least 3, but not greater than 48 hours duration. Most patients (14) were in the hospital at the time ranolazine was administered. Age, sex, echocardiographic data, associated health conditions and structural heart disease were recorded. Successful conversion was defined as restoring sinus rhythm within 6 hours of ranolazine administration. RESULTS: All but 1 patient had some form of structural heart disease and all but 2 patients had left atrial enlargement. Thirteen of 18 patients converted to sinus rhythm. No pro-arrhythmic effects, hemodynamic instability, adverse rate effects, or perceived intolerance (other than constipation) were noted. The 72% conversion rate was comparable to other reported "pill in the pocket" protocols. CONCLUSIONS: High dose oral ranolazine shows utility as a possible safe agent to convert new or paroxysmal AF. Lack of blinded controls and small numbers limits the power of this observation.

Cardiovascular risk profile: comparison between white and Southeast Asian youth in Wausau SCHOOL Project.

INTRODUCTION: The Wausau School Children Have Early Onset Of Leading Risk Factors of Cardiovascular Disease and Diabetes Mellitus (SCHOOL) Project is a community-based effort to assess the cardiovascular (CV) health of students in the Wausau School District (WSD). It has been previously demonstrated that risk factors for CV disease are prevalent and increase with age. Wausau is also a major relocation center for Southeast Asian (SEA) immigrants. Few data are available on the CV health of SEA immigrants. This investigation compares the relative frequency of CV risk factors in SEA and white students in the WSD. METHODS: A random selection of 2nd, 5th, 8th, and 11th grade students provided demographic data, health history, sex-adjusted body mass index (BMI), fasting glucose levels, blood pressure levels, and nuclear magnetic resonance lipid profiles (Liposcience). This included 519 white and 48 SEA students. To assess for CV disease risk factors, study participants were examined for dyslipidemia, hypertension, impaired fasting glucose levels, above-normal body weight, and history of smoking. RESULTS: Risk factors for CV disease increased with age for both white and SEA participants. The mean number of risk factors in SEA participants was 1.63 compared to 1.12 for white participants (P=0.016). The mean number of risk factors also increased significantly across grade levels (P=0.001). There was no difference in mean BMI values (P=0.58). No significant differences were found in triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, blood pressure, or glucose values. Dyslipidemia was present in 53% of SEA students and 42% of white students (P=0.14). CONCLUSION: CV risk factors are common in school-age children, and the number of risk factors increases with age. SEA students presented a greater prevalence of CV risk factors than white students, but were not significantly more overweight. Interestingly, in a relatively short time period after immigration, first-generation SEA youth have developed a number of CV risk factors equal to or greater than those of their white counterparts.

The effect of ranolazine on maintaining sinus rhythm in patients with resistant atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) may arise out of anomalous impulse activity at atrial venous junctions. Triggered activity may be a source of abnormal impulse activity. Ranolazine is an anti-anginal agent, which inhibits normal and abnormal late Na+ channel current in the ventricle and peak Na+ channel current in the atrium. This produces an energy sparing effect and stabilizes cardiac membranes. Ranolazine is a potent inhibitor of triggered activity. The purpose of this report is to describe our initial experience with ranolazine used in patients with resistant AF. METHODS: Seven patients (4 males, 3 females, 67 +/- 9 years) who developed recurrent AF within hours to a few days of restoring sinus rhythm despite AF ablation and /or failing one or more anti-arrhythmic agents were started on ranolazine (500-1000 mg/twice/day) after stopping all other anti-arrhythmic therapy. All but one patient had some form of associated structural heart disease. RESULTS: Two patients received no apparent benefit from ranolazine developing recurrent AF within 2 days. All other patients derived significant benefit. Four patients have experienced no recurrent AF. The other patient relapsed at 3 months and again at 6 months. The mean time in sinus rhythm to date, or to the first relapse, for the five responders was 27 +/- 11 weeks. No clinically evident pro-arrhythmic episodes occurred. CONCLUSION: Ranolazine was helpful in maintaining sinus rhythm in the majority of patients in which more established measures had failed. A controlled prospective trial is warranted to further investigate the efficacy of ranolazine in AF.

Ranolozine-induced suppression of ventricular tachycardia in a patient with nonischemic cardiomyopathy: a case report.

Ranolazine is an antianginal agent, which inhibits the abnormal inward Na(+) current and by this inhibition decreases diastolic cardiomyocyte calcium levels and improves electrical stability. Ranolazine has also been shown to be a potent inhibitor of after depolarizations and triggered activity. In this case report, we describe the dramatic antiarrhythmic effects of ranolazine in a patient with nonischemic cardiomyopathy who had malignant ventricular tachycardia. Further research on the antiarrhythmic properties of ranolazine appears warranted.

Benefit of adding pioglitazone to statin therapy in non-diabetic patients with the metabolic syndrome.

Statins frequently do not control all of the lipid abnormalities found in patients with the metabolic sydrome. Pioglitizone (PIO), an insulin sensitizing agent, has been shown to have favorable lipid effects in diabetic patients. Little information is available regarding the effect of combined statin and PIO therapy in non-diabetic patients with the metabolic syndrome. We report our experience of adding PIO to statin therapy in non-diabetic patients with the metabolic syndrome. Pioglitazone was administered to 24 non-diabetic patients in our lipid clinic who were already on a statin yet continued to have significant lipid abnormalities. All patients had characteristic lipid abnormalities and clinical features of the metabolic syndrome. The treatment period was 59+/-29 (range 7-123) weeks. Lipid profiles, fasting glucose, and alanine aminotransferase were assessed before and at least 6 weeks after pioglitazone was added to statin. Triglyceride levels decreased from 307+/-295mg/dL to 173+/-129mg/dL (P=0.003), non-high-density lipoprotein cholesterol (non-HDL) decreased from 151+/-53mg/dL to 130+/-49mg/dL, (P=0.003), and high-density lipoprotein cholesterol (HDL) levels increased from 42+/-11mg/ dL to 45+/-12mg/dL, (P=0.039). The addition of PIO to statin in non-diabetic patients with metabolic sydrome produced significant additional benefits in the lipid profile over statin monotherapy. Favorable effects were seen in triglycerides, HDL, and non-HDL levels. Study limitations include: this is a small non-blinded observational study in which patients served as their own controls. The duration of combination therapy and type of statin employed were variable.

School children have leading risk factors for cardiovascular disease and diabetes: the Wausau SCHOOL project.

INTRODUCTION: Risk factors for cardiovascular disease and diabetes acquired in childhood commonly persist in later life and are particularly strong predictors of subclinical atherosclerosis in young adults. A rising tide of obesity and other lifestyle-related risk factors threatens to negate much of the success achieved in the prevention and treatment of these diseases. The SCHOOL project (School Children Have Leading Risk Factors for Cardiovascular Disease and Diabetes), was designed to measure the prevalence and magnitude of known risk factors in school-age children in Wausau, Wis. METHODS: Demographic data, anthropomorphic measures, family health history, diet and activity indices, and numerous laboratory measures were collected from a representative sample of students in grades 2, 5, 8, and 11. RESULTS: Clinically important disturbances of lipid metabolism were very common, even in the youngest participants. Of the children studied, 39% had at least 1 lipid abnormality and 22% had 2 or more. Abnormal blood pressure, overweight, and cigarette smoking were present in 29%, 16%, and 11% respectively. While elevated fasting glucose levels were uncommon, insulin resistance was noted in 25% of the sampled population and nearly 50% of sampled children with a body mass index greater than the 85th percentile in this survey. The number of children with multiple risk factors rose dramatically with age. By 11th grade, 38% of those surveyed had 2 or more risk factors and 23% had 3 or more. CONCLUSIONS: Using conservative definitions, significant abnormalities of lipid metabolism and other risk factors for cardiovascular disease and diabetes were common in our children. Risk profiles in older adolescents were worse than in the younger students and similar to what would be expected for adults with known coronary heart disease. In our community there is a growing consensus that we must take advantage of the multiple opportunities that exist to favorably alter the lifestyle patterns that put our children at risk.

Effect of body mass index on insulin resistance and lipids in prepubertal and postpubertal children: SCHOOL observations.

As part of the School Children Have Early Onset of Leading Risk Factors for Cardiovascular Disease and Diabetes Mellitus (SCHOOL) project, this study examines the effect of elevated body mass index on metabolic parameters and its relationship to insulin resistance in prepubertal and postpubertal students from the Wausau School District in central Wisconsin. Two hundred forty-seven nondiabetic students were randomly selected (125 prepubertal [2nd graders] and 122 postpubertal [11th graders]). Waist/hip ratio and body mass index corrected for age and sex were calculated. Fasting insulin, glucose, and nuclear magnetic resonance lipid profiles were measured. Relative insulin resistance was defined as quantitative insulin sensitivity check index > 1 SD below the mean of normal-weight children. Twenty-eight percent of 2nd graders and 33% of 11th graders were overweight. Relative insulin resistance was present in 47% of overweight 2nd graders and 51 % of overweight 11th graders and was associated with higher triglycerides, lower high-density lipoprotein, smaller low-density lipoprotein particles and, in 11th graders, higher waist/hip ratio. Relative insulin resistance prevalence is high among overweight children and adolescents. Biomarkers of increased risk of adverse cardiovascular outcomes are already present in overweight school children.

Stroke and atrial fibrillation following cardiac surgery.

OBJECTIVE: Stroke is an occasional devastating complication of cardiac surgery. Transient atrial fibrillation (AF) is a frequent complication of cardiac surgery. Emboli originating from the fibrillating left atrium are a known cause of stroke in the non-surgical setting. The purpose of this quality improvement initiative, conducted by the Wausau Heart Institute, was to characterize strokes after cardiac surgery and to investigate the relationship between AF and the occurrence of postoperative strokes. METHODS: We conducted a retrospective record review of all patients undergoing cardiac surgery utilizing cardiopulmonary bypass without associated carotid surgery at our institution between January 1, 1993 and June 30, 1999. The occurrence of strokes and AF was noted. The timing of the AF (duration and relationship to surgery) was recorded. RESULTS: Of the 2104 eligible patients, strokes occurred in 68 (3.2%). In 18 patients (27%), stroke was immediately apparent as the patient recovered from anesthesia (intra-operative stroke). Fifty of the 68 strokes (74%) were acquired following the immediate operative period after the patient awoke from anesthesia neurologically intact (postoperative stroke). Postoperative stroke occurred in 2.1% of patients undergoing coronary bypass surgery only, in 2.2% if valve surgery only was performed, and 4.6% if both valve and bypass surgery were performed. AF occurred in 700 patients (33%). The incidence of postoperative stroke was 5.4% in patients with AF and 0.89% in those without AF (P < 0.001). Of those patients suffering a postoperative stroke, 76% had AF following cardiac surgery, compared to 32% if a postoperative stroke did not occur (P < 0.001). Carotid bruits were present in 7 (14%) of the patients with postoperative stroke. Carotid ultrasound studies were performed in 32 patients (63%) and a lesion of > 70% was found in 8 patients (25%). Cerebral lesions contralateral to the stenotic carotid artery occurred in 3 of these 8 patients. CONCLUSION: Most strokes complicating cardiac surgery occur in patients without significant carotid disease, and are acquired after the patient awakens neurologically intact. The high incidence of postoperative AF in these patients suggests a possible embolic cause for some of the strokes. As such, some postoperative strokes may be preventable.