In a consecutive case series, cross-sectional study of 401 women referred for hyperlipidemia therapy, (110 [27%] on estrogen replacement therapy [ERT]), we assessed whether ERT-mediated thrombophilia and heritable thrombophilia (20210 G[rarr ]A prothrombin gene [PTG], Factor V Leiden gene mutation [FV]) interacted as risk factors for atherothrombotic cardiovascular disease (ATCVD). Thirty-eight percent of women (152/401) had [ge ] 1 ATCVD event, 57 (14%) had [ge ] 2 ATCVD events. Fifteen women (3.7%) were PTG heterozygotes, 24 (6.0%) were FV heterozygotes, (there was 1 double heterozygote [0.25%]); 363 (91%) were wild-type normal for both genes. Of the 152 women with [ge ] 1 ATCVD event, 21 (14%) had [ge ] 1 thrombophilic gene mutation, versus 17/249 (7%) without events (X2 = 5.4, P = .02). In women on ERT and with both genes wild-type normal, 23 of 96 (24%) had [ge ] 1 ATCVD event versus 8 of 14 (57%) on ERT and with [ge ] 1 thrombophilic mutation, X2 = 6.6, P = .01. By stepwise logistic regression, in 401 women (152 with [ge ] 1 ATCVD event, 249 no events), positive explanatory variables for ATCVD included FV and/or PTG (risk odds ratio, 2.59, 95% confidence interval [CI] 1.26 to 5.36, P = .01) and a PTG*ERT interaction term (risk odds ratio, 2.27, 95% CI 1.36 to 3.79, P = .0017). After deleting 23 FV heterozygotes and 14 PTG heterozygotes and 1 double heterozygote from the 401 women, ERT was protective against ATCVD events, with a risk odds ratio of 0.50 and 95% CI of 0.29 to 0.87 P = .014. PTG and FV may increase risk for ATCVD, particularly in the presence of ERT, whereas ERT may be protective against ATCVD when PTG and FV are absent.

In a consecutive case series, cross-sectional study of 275 women referred for therapy of hyperlipidemia, (75 [27%] on estrogen replacement therapy [ERT]), our specific aim was to determine whether ERT-mediated thrombophilia and heterozygosity for the thrombophilic 20210 G/A prothrombin gene mutation interacted as risk factors for atherothrombotic cardiovascular disease (ATCVD). Of the 275 women, 100 (36%) had ATCVD; 10 (3.6%) were heterozygous for the 20210 G/A prothrombin gene mutation. In women without the 20210 G/A prothrombin gene mutation, 15 of 71 (21%) on ERT had ATCVD versus 78 of 194 (40%) not on ERT (X2 = 8.31, P = .004). By stepwise logistic regression, in 261 women with ATCVD risk factor data, positive explanatory variables for ATCVD included the 20210 G/A prothrombin mutation (risk odds ratio, 5.8; 95% confidence intervals [CI], 1.4 to 30.2; P = .021) and a 20210 G/A prothrombin gene mutation*ERT interaction term (risk odds ratio, 2.70; 95% CI, 1.4 to 5.4; P = .004). ATCVD events were more likely in 2 subgroups of women (ERT minus [−] and 20210 G/A prothrombin gene mutation −) or (ERT plus [+] and 20210 G/A prothrombin gene mutation +), P = .004. Other positive explanatory variables for ATCVD events included age (P = .004), triglycerides (P = .012), lipoprotein (a) (P = .03), and homocysteine (P = .032). ERT may be protective against ATCVD when the thrombophilic 20210 G/A prothrombin gene mutation is absent, whereas the 20210 G/A prothrombin gene mutation may increase risk for ATCVD, particularly in the presence of ERT. We suggest that the 20210 G/A prothrombin gene mutation be measured in all women on ERT or before beginning ERT to identify those heterozygous for the thrombophilic prothrombin gene mutation (4%) in whom ERT is contraindicated because of increased risk for ATCVD and thromboembolism, and a second, much larger group of women without the 20210 G/A prothrombin gene mutation (96%) in whom ERT may possibly reduce risk for ATCVD.

We studied 31 nondiabetic, habitually (> or =5 years) morbidly obese subjects (mean +/- SD body mass index [BMI] 43 +/- 8.7, median 43). Our specific aim was to determine whether metformin (2.55 g/d for 28 weeks) would ameliorate morbid obesity and reduce centripetal obesity; lipid and lipoprotein cholesterol, insulin, and leptin levels; and plasminogen activator inhibitor activity (PAI-Fx), risk factors for coronary heart disease (CHD). The patients were instructed to continue their prestudy dietary and exercise regimens without change. After 2 baseline visits 1 week apart, the 27 women and 4 men began receiving metformin, 2.55 g/d, which was continued for 28 weeks with follow-up visits at study weeks 5, 13, 21, and 29. Daily food intake was recorded by patients for 7 days before visits then reviewed with a dietitian. Kilocalories per day and per week were calculated. At each visit, fasting blood was obtained for measurement of lipid profile, insulin, leptin, and PAI-Fx. The mean +/- SD kilocalories consumed per day, 1,951 +/- 661 at entry, fell by week 29 to 1,719 +/- 493 (P =.014) but did not differ at weeks 5, 13, and 21 from that at week 29 (P >.2). Weight fell from 258 +/- 62 pounds at entry to 245 +/- 54 pounds at week 29 (P =.0001). Girth was reduced from 51.8 +/- 6.2 to 49.2 +/- 4.5 inches (P =.0001). Waist circumference fell from 44.0 +/- 6.4 inches to 41.3 +/- 5.9 (P =.0001). The waist/hip ratio fell from 0.85 +/- 0.09 to 0.84 +/- 0.09 (P =.04). Fasting serum insulin, 28 +/- 15 microU/mL at entry, fell to 21 +/- 11 microU/mL at week 29 (P =.0001), and leptin fell from 79 +/- 33 ng/mL to 55 +/- 27 ng/mL (P =.0001). On metformin, there were linear trends in decrements in weight, girth, waist circumference, waist/hip ratio, insulin, and leptin throughout the study period (P <.007). Low-density lipoprotein (LDL) cholesterol, 126 +/- 34 mg/dL at study entry, fell to 112 +/- 43 mg/dL at week 29 (P =.001), with a linear trend toward decreasing levels throughout (P =.036). By stepwise linear regression, the higher the entry weight, the larger the reduction in weight on metformin therapy (partial R(2) = 31%, P =.001). The greater the reduction in kilocalories consumed per day, the greater the decrease in weight on metformin therapy (partial R(2) = 15%, P =.011). The higher the waist/hip ratio at entry, the greater its reduction on metformin therapy (partial R(2) = 11%, P =.004). The higher the entry serum leptin, the greater its reduction on metformin therapy (partial R(2) = 29%, P =.002). The greater the reduction in insulin on metformin, the greater the reduction in leptin (partial R(2) = 8%, P =.03). The higher the entry PAI-Fx, the greater the reduction in PAI-Fx on metformin (partial R(2) = 43%, P =.0001). Metformin safely and effectively reduces CHD risk factors (weight, fasting insulin, leptin, LDL cholesterol, centripetal obesity) in morbidly obese, nondiabetic subjects with BMI > 30, probably by virtue of its insulin-sensitizing action.

In a cross-sectional study of 293 nondiabetic patients (169 men and 124 women) referred for the diagnosis and treatment of hyperlipidemia, our specific aim was to determine whether fasting serum insulin independently contributes to the prediction of atherosclerotic cardiovascular disease (ASCVD) status. Of the 169 men and 124 women, 65 (38%) and 44 (35%), respectively, had ASCVD with at least one of the following: unstable angina, myocardial infarction (MI), angioplasty, coronary artery bypass graft (CABG), cluadication, transient ischemic attack, or ischemic stroke. In addition, 42% and 38% had fasting hyperinsulinemia (≥20 μU/mL). Fasting serum insulin of 20 μU/mL or higher was very in women (59% to 100%) and men (67% to 88%) when hypertension, obesity, top-decile triglyceride (TG), and bottom-decile high-density lipoprotein cholesterol (HDLC) were concurrent in various combinations. ASCVD events (present or absent) were dependent variables in a stepwise logistic regression model with explanatory variables including age, gender, race, hypertension, cigarette smoking, ASCVD in first-degree relatives at age 55 years or less, Quetelet Index, fasting serum insulin, a gender × insulin interaction term, anticardiolipin antibodies (ACLAs) IgG and IgM, total cholesterol to HDLC ratio. TG, lipoprotein(a) [Lp(a)], and homocysteine. The risk odds ratio for ASCVD (109 events and 184 nonevents) for subjects with top-decile insulin (v the bottom nine deciles was 3.71 with a 95% confidence interval (CI) of 1.62 to 8.9 (P = .002). For patients with MI and/or CABG and/or angioplasty ([MCA] 63 events and 184 nonevents), the risk odds ratio for top-decile insulin versus the rest was 5.07 (95% CI, 1.83 to 14.8, P = .002). For patients with MCA at age 55 or less, the gender × insulin interaction term was significant (P = .0004); the risk odds ratio for men with top-decile insulin was 13.28 (95% CI, 3.82 to 51.65, P = .0001). Hyperinsulinemia is very common in nondiabetic hyperlidemic women and men. Fasting serum insulin, a crude, simple, practical, and inexpensive measure, independently and uniformly improved the prediction of ASCVD status beyond traditional risk factors and lipid variables in patients referred for treatment of hyperlipidemia.

Thrombophilic anticardiolipin antibodies (ACLAs) are independent risk factors for atherosclerotic vascular disease, We suggest that ACLAs IgG and IgM be routinely measured as ancillary atherothrombotic risk factors in all patients with atherosclerotic vascular disease events, in those at high risk for atherosclerotic vascular disease, and in those in whom thrombosis is a major pathoetiology.

Estrogen replacement therapy (ERT), which produces acquired resistance to activated protein C when superimposed on heritable resistance to activated protein C (the mutant Factor V Leiden trait), may promote venous and arterial thrombosis. In a cross-sectional study of 423 women referred for hyperlipidemic therapy (93 of whom [22%] were on ERT), our specific aim was to determine whether ERT and heterozygosity for the Factor V Leiden mutation and/or resistance to activated protein C interacted as risk factors for atherothrombosis. Of the 423 women, 168 (40%) had atherothrombosis, 19 (4%) were heterozygous for Factor V Leiden mutation or had resistance to activated protein C <2 (Factor V Leiden mutation+), and 404 were wild-type normal for the Factor V gene and/or had resistance to activated protein C > or =2 (Factor V Leiden mutation-). By stepwise logistic regression, positive explanatory variables for atherothrombosis included hypertension (p = 0.002), age (p = 0.003), relatives with atherothrombosis (p = 0.002), anticardiolipin antibody immunoglobulin-M (p = 0.02), and a Factor V Leiden mutation*ERT interaction term where atherothrombosis events were more likely in 2 subgroups of women (ERT- and Factor V Leiden mutation-) or (ERT+ and Factor V Leiden mutation+) (p = 0.02). High-density lipoprotein cholesterol was inversely associated with atherothrombosis (p = 0.004). In a separate logistic regression model for the 213 women with a polymerase chain reaction measurement of the Factor V gene, ERT was protective (p = 0.008); the Factor V Leiden mutation was positively associated with atherothrombosis (p = 0.05). The atherothrombosis odds ratio risk for ERT (yes vs no) was 0.36 (95% confidence intervals [CI] 0.16 to 0.74, p = 0.007). The atherothrombosis risk odds ratio in women heterozygous for the Factor V Leiden mutation (vs normal) was 2.00 (95% CI 1.02 to 4.22, p = 0.05). ERT may be protective against atherothrombosis when the Factor V Leiden mutation is absent, whereas the Factor V Leiden mutation may increase risk for atherothrombosis, particularly in the presence of ERT. We suggest that the Factor V Leiden mutation be measured in all women on ERT or before beginning ERT to identify those heterozygous for the Factor V Leiden mutation (4%), in whom ERT is relatively or absolutely contraindicated because of increased risk for atherothrombosis and thromboembolism. A second, much larger group of women will also be identified without the factor V Leiden mutation (96%), in whom ERT may reduce the risk for atherothrombosis.

In clinical practice 5–10% of patients receiving statins develop myopathy, a side effect that had been systematically underestimated in the randomized controlled trials with statins. The most common manifestation of myopathy is muscle pain (usually symmetrical, involving proximal muscles) without creatinine kinase (CK) elevation or less frequently with mild CK elevation. Clinically significant rhabdomyolysis (muscle symptoms with CK elevation > 10 times the upper limit of normal and with creatinine elevation) is extremely rare. Myopathy complicates the use of all statins (class effect) and is dose-dependent. The pathophysiologic mechanism of statin-associated myopathy is unknown and probably multifactorial. The risk of statin-associated myopathy can be minimized by identifying vulnerable patients (i.e. patients with impaired renal or liver function, advanced age, hypothyroidism, etc.) and/or by eliminating-avoiding statin interactions with specific drugs (cytochrome P-450 3A4 inhibitors, gemfibrozil, etc.). In symptomatic patients, the severity of symptoms, the magnitude of CK elevation and the risk/benefit ratio of statin continuation should be considered before statin treatment is discontinued. Potential strategies are the use of the same statin at a lower dose and if symptoms recur the initiation of fluvastatin XL 80 mg daily or rosuvastatin intermittently in low dose (5–10 mg), combined usually with ezetimibe 10 mg daily. Failure of these approaches necessitates the use of non-statin lipid lowering drugs (ezetimibe, colesevelam). In order to provide evidence based recommendations for the appropriate management of statin-intolerant patients we need randomized clinical trials directly comparing the myopathic potential of different lipid-lowering medications at comparable doses.

In 482 patients sequentially referred for diagnosis and therapy of hyperlipidemia, our specific aim was to determine the prevalence of homocysteinemia, to assess whether it was independently associated with atherosclerotic vascular disease, and to determine how effectively high homocysteine could be treated with folic acid and pyridoxine. Of the 482 patients, 18 (3.7%) had high homocysteine (≥16.2 μmol/L, median = 19), 31 had high cystathionine (≥342 nmol/L) with normal homocysteine (median = 12), and 433 had normal cystathionine and homocysteine (median = 9). Of the 18 patients with high homocysteine, 13 (72%) had atherosclerotic vascular disease, much higher than the 44% (192 of 433 patients) with normal homocysteine (chisquare = 5.4, p = 0.02). In the 18 kindreds with a homocysteinemic proband, 14 (78%) had ≥1 firstdegree relatives with atherosclerotic vascular disease before age 65, compared with 50% (215 of 433) of the families where the proband had normal homocysteine (chi-square = 5.5, p = 0.02). In the 482 patients already at high risk for atherosclerotic vascular disease by virtue of hyperlipidemia, when assessed by logistic regression, homocysteine was an independent positive predictor of atherosclerotic vascular disease (p = 0.007); relative risk for atherosclerotic events was 2.8 times higher (p = 0.0004) in patients with top (≥11.4 μmol/L) than with bottom (<6.9 μmol/L) quintile homocysteine. After 15 weeks of folic acid (5 mg/day) and pyridoxine (100 mg/day) therapy in 10 patients with high homocysteine, median homocysteine normalized, decreasing from 18 to 11 μmol/L (p = 0.001). To best quantitate and ameliorate risk for atherosclerotic vascular disease, homocysteine should routinely be measured at least once in hyperlipidemic patients at high risk for atherosclerosis and, if high, should be treated.

In recent years, new-onset hypothyroidism was extensively reported in patients receiving sunitinib for malignancy. Effects of sunitinib on serum lipids are not described, however a hyperlipidemic state is commonly observed in hypothyroid patients. Here we report about the incidence and severity of hypercholesterolemia and hypertriglyceridemia in a cohort of patients receiving sunitinib for metastatic renal cell carcinoma.Thyroid function tests, serum triglycerides, and cholesterol were prospectively evaluated in 39 consecutive metastatic renal cell carcinoma patients, who were receiving sunitinib as a first-line treatment. Incidence of hyperlipidemia, thyroid function impairment, and their possible relationship were investigated.Thyroid function tests, serum cholesterol, and triglycerides were assessed at baseline and before the beginning of each sunitinib cycle. During treatment, median triglyceride levels increased up to 271.3 mg/dL, and median cholesterol increased up to 234.7 mg/dL (+113% and +22%, respectively). A hyperlipidemic state developed in 27 patients (69.2%) within a mean time of 1.8 six-week cycles (range, 1-5 cycles) and persisted during treatment. Hypothyroidism was observed in 20 patients (51.2%) and usually developed within 2.3 cycles. Because hypothyroidism and hyperlipidemia developed at different time points of treatment and among different patients, our results failed to demonstrate a correlation between these adverse events.New-onset hyperlipidemia was observed in an increased percentage of patients taking sunitinib. The mechanism of this side effect is still unclear. We recommend careful monitoring of serum lipid levels during sunitinib administration to recognize possible consequences, especially on cardiovascular health.

A rare case of cruciate paralysis is reported in a 39-year-old man following a motor-vehicle accident. The differentiation of this syndrome from a central cervical spinal cord injury is delineated.