Naseer Khan

Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients.

Our specific aims were to determine whether low serum 25 (OH) vitamin D (D2 + D3) (<32 ng/mL) was associated with myalgia in statin-treated patients and whether the myalgia could be reversed by vitamin D supplementation while continuing statins. After excluding subjects who took corticosteroids or supplemental vitamin D, serum 25 (OH) D was measured in 621 statin-treated patients, which consisted of 128 patients with myalgia at entry and 493 asymptomatic patients. The 128 myalgic patients had lower mean +/- standard deviation (SD) serum vitamin D than the 493 asymptomatic patients (28.6 +/- 13.2 vs 34.2 +/- 13.8 ng/mL, P < 0.0001), but they did not differ (p > 0.05) by age, body mass index (BMI), type 2 diabetes, or creatine kinase levels. By analysis of variance, which was adjusted for race, sex, and age, the least square mean (+/- standard error [SE]) serum vitamin D was lower in the 128 patients with myalgia than in the 493 asymptomatic patients (28.7 +/- 1.2 vs 34.3 +/- 0.6 ng/mL, P < 0.0001). Serum 25 (OH) D was low in 82 of 128 (64%) patients with myalgia versus 214 of 493 (43%) asymptomatic patients (chi(2) = 17.4, P < 0.0001). Of the 82 vitamin-D-deficient, myalgic patients, while continuing statins, 38 were given vitamin D (50,000 units/week for 12 weeks), with a resultant increase in serum vitamin D from 20.4 +/- 7.3 to 48.2 +/- 17.9 ng/mL (P < 0.0001) and resolution of myalgia in 35 (92%). We speculate that symptomatic myalgia in statin-treated patients with concurrent vitamin D deficiency may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle.

Vitamin D deficiency, myositis–myalgia, and reversible statin intolerance

Abstract Objective: In 150 hypercholesterolemic patients, unable to tolerate ≥1 statin because of myositis-myalgia, selected by low (<32 ng/ml) serum 25 (OH) vitamin D, we prospectively assessed whether vitamin D supplementation with resolution of vitamin D deficiency would result in statin tolerance, free of myositis–myalgia. Research design and methods: We studied 74 men, 76 women, median age 60, 131 white, 17 black and 2 other. On no statins, 50,000 units of vitamin D was given twice a week for 3 weeks, and then continued once a week. After 3 weeks on vitamin D, statins were restarted. Patients were re-assessed on statins and vitamin D every 3 to 4 months, with serial measures of serum 25 (OH) vitamin D, creatine phosphokinase (CPK), LDL cholesterol (LDLC) and assessment of myositis–myalgia. Main outcome measures: Percentage of patients myalgia-free on vitamin D plus reinstituted statins, serum 25 (OH) vitamin D, CPK, and LDLC on reinstituted statins and concurrent vitamin D supplementation. Results: On vitamin D supplementation plus re-instituted statins for a median of 8.1 months, 131 of the 150 patients (87%) were free of myositis–myalgia and tolerated the statins well. Serum 25 (OH) vitamin D increased from median 21 to 40 ng/ml (p < 0.001), and normalized (≥32 ng/ml) in 117 (78%) of 150 previously vitamin D deficient, statin-intolerant patients. Median LDLC decreased from 146 mg/dl to 95 mg/dl, p < 0.001. Conclusion: Symptomatic myositis–myalgia in hypercholesterolemic statin-treated patients with concurrent serum 25 (OH) vitamin D deficiency may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle causing myalgia.

Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia

Our specific aim was to describe thrombosis (osteonecrosis of the hips, pulmonary embolism, and amaurosis fugax) after exogenous testosterone was given to men with no antecedent thrombosis and previously undiagnosed familial thrombophilia. After starting testosterone patch or gel, 50 mg/day or intramuscular testosterone 400 mg IM/month, 2 men developed bilateral hip osteonecrosis 5 and 6 months later, and 3 developed pulmonary embolism 3, 7, and 17 months later. One man developed amaurosis fugax 18 months after starting testosterone gel 50 mg/day. Of these 6 men, 5 were found to have previously undiagnosed factor V Leiden heterozygosity, 1 of whom had ancillary MTHFR C677T homozygosity, and 2 with ancillary MTHFR C677T-A1298C compound heterozygosity. One man had high factor VIII (195%), factor XI (179%), and homocysteine (29.3 umol/L). Thrombotic events after starting testosterone therapy are associated with familial thrombophilia. We speculate that when exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on familial thrombophilia, thrombosis occurs. Men sustaining thrombotic events on testosterone therapy should be screened for the factor V Leiden mutation and other familial and acquired thrombophilias.

Should high creatine kinase discourage the initiation or continuance of statins for the treatment of hypercholesterolemia

Patients with high low-density lipoprotein cholesterol (LDLC) and asymptomatic high creatine kinase (CK) (>or=250 but <2500 IU/L, 10x the laboratory upper normal limit [UNL]) are often not started on statins or have statins stopped because of concern about myositis-rhabdomyolysis. In the current report, we prospectively examined the hypothesis that asymptomatic patients with high CK (>or=250 but <2500 IU/L) tolerate statins well at doses reducing LDLC to target, less than 100 mg/dL, without development of myalgia-myositis. We assessed outcomes of 3 groups of patients referred to us because of asymptomatic high CK (>or=250 but <2500 IU/L)--1 group (n = 29) on statins at referral and continued on statins, 1 group (n = 20) not on statins and started on statins, and 1 group (n = 19) not on statins and not given statins--all restudied 1 month after entry and then every 3 months. Of the 68 patients, 59 (87%) had CK greater than 1 to 3 times the UNL, 7 (10%) had CK greater than 3 to 5 times the UNL, and 2 (3%) had CK greater than 5 to 10 times the UNL. After 1.2 months of follow-up in 29 statin-->statin patients, median CK fell from 353 to 301 (P = .0018) and was 287 (P = .015) after 4 months. After 1.3 months of follow-up in 20 no statin-->statin patients, median CK fell from 397 to 292 (P = .0094) and was 419 after 4.1 months. After 1.1 months of follow-up in 19 no statin-->no statin patients, median CK fell from 392 to 323 (P = .14) and was 271 (P = .029) after 4.2 months. By repeated-measures analysis, there were no differences in entry CK among the 3 treatment groups; CK fell (P = .04) in the no statin-->no statin patients. Despite high baseline CK (48 patients with CK 1-5x the UNL, 1 with CK 5-10x UNL), no patients during follow-up on statins developed CK greater than 10 times the UNL (2500 IU/L), none discontinued statins or reduced statin dose because of myalgia-myositis, and there was no rhabdomyolysis. High pretreatment CK, particularly 1 to 5 times the UNL, should not be an impediment to start or continue statins to lower LDLC.

T−786C polymorphism of the endothelial nitric oxide synthase gene and neuralgia-inducing cavitational osteonecrosis of the jaws

OBJECTIVE We hypothesized that, similar to idiopathic hip osteonecrosis, the T-786C mutation of the endothelial nitric oxide synthase (eNOS) gene affecting nitric oxide (NO) production was associated with neuralgia-inducing cavitational osteonecrosis of the jaws (NICO). DESIGN In 22 NICO patients, not having taken bisphosphonates, mutations affecting NO production (eNOS T-786C, stromelysin 5A6A) were measured by polymerase chain reaction. Two healthy normal control subjects were matched per case by race and gender. RESULTS Homozygosity for the mutant eNOS allele (TT) was present in 6 out of 22 patients (27%) with NICO compared with 0 out of 44 (0%) race and gender-matched control subjects; heterozygosity (TC) was present in 8 patients (36%) versus 15 control subjects (34%); and the wild-type normal genotype (CC) was present in 9 patients (36%) versus 29 controls (66%) (P = .0008). The mutant eNOS T-786C allele was more common in cases (20 out of 44 [45%]) than in control subjects (15 out of 88 [17%]) (P = .0005). The distribution of the stromelysin 5A6A genotype in cases did not differ from control subjects (P = .13). CONCLUSIONS The eNOS T-786C polymorphism affecting NO production is associated with NICO, may contribute to the pathogenesis of NICO, and may open therapeutic medical approaches to treatment of NICO through provision of L-arginine, the amino-acid precursor of NO.

Enoxaparin-metformin and enoxaparin alone may safely reduce pregnancy loss

Polycystic ovary syndrome (PCOS), thrombophilia, and hypofibrinolysis are associated with recurrent pregnancy loss (RPL) and spontaneous abortion (SAB). In 28 Caucasian women, 21 women with PCOS (4 with previous thrombosis, 18 with 1 SAB or more, and 20 with 1 coagulation disorder or more), and 7 women with coagulation disorders-thrombi, we speculated that prospective treatment with enoxaparin-metformin or enoxaparin alone would successfully and safely promote healthy live births compared with previous untreated pregnancies. In 21 women with PCOS, metformin (1.5-2.55 g/day) was given before and during pregnancy with concurrent enoxaparin (60 mg/day). Of 21 PCOS women, 19 women had 40 previous untreated pregnancies, 7 had live births (18%), 3 had elective abortions (ABs) (8%), and 30 had SABs (75%). On enoxaparin-metformin, these 19 women had 24 pregnancies, 20 live births (83%), and 4 SABs (17%); the SAB rate was 4.4-fold lower than previous untreated pregnancies (McNemars s = 20.8, P < 0. 0001). Two women with PCOS without previous pregnancies, but with previous thrombosis, had 2 pregnancies on enoxaparin-metformin and 2 live births. Of the 7 women with coagulation disorders-thrombi, 4 had 15 previous pregnancies without enoxaparin, with 6 live births (40%), 8 SABs (53%), and 1 elective AB (7%). On enoxaparin, these 4 women had 4 pregnancies, with 4 (100%) live births (McNemars s = 8.0, P = 0.005). The other 3 women with coagulation disorders-thrombi had 4 pregnancies on enoxaparin with 4 live births. No adverse maternal-fetal side effects were reported on enoxaparin alone or enoxaparin-metformin. Enoxaparin-metformin reduces pregnancy loss in women with PCOS-coagulation disorders and in women with coagulation disorders-thrombi.

Titrating lovaza from 4 to 8 to 12 grams/day in patients with primary hypertriglyceridemia who had triglyceride levels >500 mg/dl despite conventional triglyceride lowering therapy

BackgroundOmega-3 fatty acids are important in treatment of severe primary hypertriglyceridemia (HTG). In 15 patients with severe primary HTG (TG >500 mg/dl despite conventional TG lowering therapy), we assessed efficacy-safety of sequential monthly treatment with Lovaza, 4 to 8 to 12 g/day.MethodsWith TG >500 mg/dl despite Type V diet, hyperinsulinemia and diabetes control, and fibric acids, Lovaza (4 g/d) was added for 1 month, and if TG remained >500 mg/dl, increased to 8 g/d for 1 month, and then to 12 g/d for 1 month, and subsequently reduced to 4 g/day for 4 months.ResultsPrimary HTG, median TG 884 mg/dl, 14 men, 1 woman, all white, age 50 ± 7 years, 12 non-diabetic, 3 with stable diabetes control. Weight and diet held stable throughout. In 5 patients, after 1, 2, and 3 months on 4 g/day, TG fell <500, mean 1390 to 234 (−83%, p<.0001), to 135 (−90%, p<.0001), and 158 mg/dl (−89%, p<.0001), with a negative TG slope, p=.0013. Non-HDLC fell from 320 to 177 (−45%, p=.001), to 152 (−53%, p=.0002), and to 163 (−49%, p=.0004), with a negative slope, p=.01. In 10 patients, with Lovaza increased from 4 to 8 to 12 g, 3 failed to respond. In 7 of these 10 patients, TG fell 37% from 1075 to 672 on 4 g (p=.006), to 577 on 8 g (−46%, p=.0009), and to 428 mg/dl (−60%, p<.0001) on 12 g/day, with a negative TG slope, p=.0018. TG on 12 g/day was lower than on 8 g/day, p =.03. Non-HDLC fell from 245 to 217 mg/dl (−11%) on 4 g/day, to 203 (−17%, p=.01) on 8 g/day, and to 192 (−22%, p=.003) on 12 g/day, with a negative slope, p=.016. Compared to pre-Lovaza baseline, no abnormal measures developed in safety tests. The 4, 8, and 12 g/d Lovaza doses were well tolerated.ConclusionTitration of Lovaza from 4 to 8 to 12 g/d safely offers an effective way to lower TG beyond conventional 4 g therapy.

High factor XI, recurrent pregnancy loss, enoxaparin

Of the 149 women with 0 pregnancy losses, 7 (5%) had factor XI level ≥150% versus 5 of 31 (16%) women with recurrent pregnancy loss. Three of the 5 women with high factor XI and recurrent pregnancy loss, with 19 previous pregnancy losses and 0 live births, were given enoxaparin during 5 subsequent pregnancies, and had 6 term live births and 1 miscarriage.

Insulin resistance and triglycerides.

In 1385 adults with primary untreated hyperlipidemia and in a population study of 339 adults (Princeton Follow-up Study [PFS]), we hypothesized that homeostasis model assessment (HOMA) insulin resistance (IR) was a significant explanatory variable for triglycerides (TG) and that IR rose in a stepwise fashion, independent of age, race, sex, and body mass index (BMI), whereas TG categories rose from less than 150 to 150 to 200, to 200 to 500, and to more than 500 mg/dL. A third hypothesis was that TG, BMI, and the ratio of TG to high-density lipoprotein cholesterol (TG/HDL-C) were significant explanatory variables for IR and that IR was inversely associated with HDL-C quintiles and positively associated with non-HDL-C quintiles. By stepwise multiple regression with age, race, sex, BMI, and IR as explanatory variables, in the 1385 patients, positive explanatory variables for TG included BMI (partial R2 = 1.3%, P < 0.0001), sex (men higher, partial R 2 = 1.1%, P = 0.0001), and IR (partial R 2 = 0.4%, P = 0.012). In the 339 PFS subjects, positive explanatory variables for TG were IR (partial R 2 = 11.4%, P < 0.0001), race (whites higher, partial R 2 = 2.1%, P = 0.005), and sex (men higher, partial R 2 = 1.4%, P = 0.019). After adjusting for age, race, sex, and BMI, in 1385 patients, HOMA IR rose while TG categories rose, with least square means of 2.64 for the TG category less than 150 mg/dL, 3.27 for 150 to 200 mg/dL, 3.85 for 200 to 500 mg/dL, and 4.12 for more than 500 mg/dL. Similarly, in the PFS, while TG categories rose, the least square means of HOMA IR rose, with 1.68 for the TG category less than 150 mg/dL, 2.34 for 150 to 200 mg/dL, and 3.03 for 200 to 500 mg/dL. Body mass index, TG, and TG/HDL-C were significant explanatory variables for IR. Homeostasis model assessment IR is a significant, potentially reversible explanatory variable for TG in patients referred because of hyperlipidemia and in population subjects.

Computer derived transient ischemic dilation ratio for identifying extensive coronary artery disease using a CZT camera and imaging in the upright position.

BackgroundTransient ischemic dilation (TID) of the left ventricle (LV) has not been validated as a marker of extensive coronary artery disease (CAD) for studies using a cadmium-zinc-telluride (CZT) camera with upright imaging.MethodsTID ratios were obtained from upright stress and rest images on a CZT camera. Separate cut-off values were determined for exercise and for regadenoson stress. The cutoffs were then applied to 28 patients with extensive CAD and 101 patients without extensive CAD.ResultsWith treadmill exercise, an upright TID ratio ≥1.16 provided a positive predictive value of 50% and a negative predictive value of 85.4% for the identification of extensive CAD. In the regadenoson group, an upright TID ratio of 1.29 provided a positive predictive value of 20% and a negative predictive value of 75.9%. Although not an independent predictor of extensive CAD in all subjects, in subjects with a normal upright LVEF, it provided a predictive value by receiver operating characteristics comparable to the SSS.ConclusionsIncreased upright TID measurements on a CZT camera are associated with extensive CAD. The upright TID measurements can serve in an adjunctive role to SSS, and may be most effective in patients with a normal upright exercise LVEF.