Background:Serum 25(OH) vitamin D levels are inversely associated with cardiovascular disease (CVD) mortality, mediated in part by independent positive relationships with high-density lipoprotein cholesterol (HDLC) and inverse relationships with low-density lipoprotein cholesterol (LDLC), triglyceride, and homocysteine.Aims:In this study, we assessed relationships between fasting serum vitamin D and lipids, lipoprotein cholesterols, and homocysteine.Materials and Methods:We studied 1534 patients sequentially referred to our center from 2007 to 2016. Fasting serum total 25(OH) vitamin D, plasma cholesterol, triglyceride, HDLC, LDLC, and homocysteine were measured. Stepwise regression models were used with total cholesterol, triglyceride, HDLC, LDLC, and homocysteine as dependent variables and explanatory variables age, race, gender, body mass index (BMI), and serum vitamin D levels. Relationships between quintiles of serum vitamin D and triglycerides, HDLC, LDLC, and homocysteine were assessed after covariance adjusting for age, race, gender, and BMI.Results:Fasting serum vitamin D was positively correlated with age, HDLC, and White race, and was inversely correlated with BMI, total and LDL cholesterol, triglyceride, and fasting serum homocysteine (P ≤ 0.0001 for all). Serum vitamin D was a significant independent inverse explanatory variable for total cholesterol, triglyceride, and LDL cholesterol, and accounted for the largest amount of variance in serum total cholesterol (partial R2 =3.6%), triglyceride (partial R2 =3.1%), and LDLC (partial R2 =2.9%) (P < 0.0001 for all). Serum vitamin D was a significant positive explanatory variable for HDLC (partial R2 = 1.4%, P < 0.0001), and a significant inverse explanatory variable for homocysteine (partial R2 = 6.0–12.6%).Conclusions:In hyperlipidemic patients, serum vitamin D was a significant independent inverse determinant of total cholesterol, LDLC, triglyceride, and homocysteine, and a significant independent positive determinant of HDLC. Thus, serum vitamin D might be protective against CVD.

We compared thrombophilia and hypofibrinolysis in 6 men with Klinefelter syndrome (KS), without previously known familial thrombophilia, who had sustained deep venous thrombosis (DVT)-pulmonary emboli (PE) or mesenteric artery thrombosis on testosterone replacement therapy (TRT). After the diagnosis of KS, TRT had been started in the 6 men at ages 11, 12, 13, 13, 19, and 48 years. After starting TRT, DVT-PE or mesenteric artery thrombosis was developed in 6 months, 1, 11, 11, 12, and 49 years. Of the 6 men, 4 had high (>150%) factor VIII (177%, 192%, 263%, and 293%), 3 had high (>150%) factor XI (165%, 181%, and 193%), 1 was heterozygous for the factor V Leiden mutation, and 1 was heterozygous for the G20210A prothrombin gene mutation. None of the 6 men had a precipitating event before their DVT-PE. We speculate that the previously known increased rate of DVT-PE and other thrombi in KS reflects an interaction between prothrombotic, long-term TRT with previously undiagnosed familial thrombophilia. Thrombophilia screening in men with KS before starting TRT would identify a cohort at increased risk for subsequent DVT-PE, providing an optimally informed estimate of the risk/benefit ratio of TRT.

BackgroundLDL cholesterol (LDLC) lowering has been revolutionized by PCSK9 inhibitors, Alirocumab (Praluent) and Evolocumab (Repatha), approved as adjuncts to maximally tolerated cholesterol lowering therapy in heterozygous (HeFH) or homozygous (HoFH) familial hypercholesterolemia, and/or clinical atherosclerotic cardiovascular disease (CVD) where LDLC lowering is insufficient.MethodsWe applied FDA and insurance eligibility criteria for PCSK9 inhibitor use in 734 hypercholesterolemic patients serially referred over 3 years who then received ≥ 2 months maximally tolerated LDLC lowering therapy with follow up LDLC ≥ 70 mg/dl, and in 50 patients approved by insurance for PCSK9 inhibitors. We documented the percentage of patients with HeFH and/or CVD who met FDA and insurance criteria for PCSK9 inhibitor therapy using LDLC goal-based guidelines.ResultsOf 734 patients with LDLC ≥ 70 mg/dl after ≥ 2 months maximally tolerated LDLC lowering therapy, 220 (30 %) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy. Another 66 (9 %) patients were statin intolerant, without HeFH or CVD. Of the 50 patients whose PCSK9 inhibitor therapy was approved for insurance coverage, 45 (90 %) had LDLC > 100 mg/dl after ≥ 2 months on maximally tolerated LDLC lowering therapy. Seventeen of these 50 patients (34 %) had HeFH without CVD (LDLC on treatment 180 ± 50 mg/dl), 15 (30 %) had CVD without HeFH (LDLC on treatment 124 ± 26 mg/dl), 14 (28 %) had both HeFH and CVD (LDLC on treatment 190 ± 53 mg/dl), and 4 (8 %) had neither HeFH nor CVD (LCLC 142 ± 11 mg/dl).ConclusionOf 734 patients referred for LDLC reduction, with LDLC ≥ 70 mg/dl after ≥ 2 months on maximally tolerated therapy, 220 (30 %) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy as an adjunct to diet-maximally tolerated cholesterol lowering therapy in HeFH or CVD. If 30 % of patients with high LDLC and HeFH-CVD are eligible for PCSK9 inhibitors, then specialty pharmaceutical pricing models (~$14,300/year) will collide with tens of millions of HeFH-CVD patients. We speculate that if there was a 50 % reduction in CVD, then there would be savings of $245 billion, in the middle of the range of estimated PCSK9 inhibitor costs of $185-342 billion. Whether the health care savings arising from the anticipated reduction of CVD events by PCSK9 inhibitors justify their extraordinary costs in broad population use remains to be determined.

BackgroundIn patients hospitalized over a 4 year period for pulmonary embolism (PE), we assessed relationships of testosterone (TT) and estrogen therapy (ET) anteceding PE in patients found to have familial-acquired thrombophilia.MethodsFrom 2011 through 2014, 347 patients were hospitalized in Cincinnati Mercy Hospitals with PE. Retrospective chart review was used to identify patients receiving TT or ET before PE; coagulation studies were done prospectively if necessary.ResultsPreceding hospitalization for PE, 8 of 154 men (5 %) used TT, and 24 of 193 women (12 %) used ET. The median number of months from the initiation of TT or ET to development of PE was 7 months in men and 18 months in women. Of the 6 men having coagulation measures, all had ≥ 1 thrombophilia, and of the 18 women having measures of coagulation, 16 had ≥ 1 thrombophilia. The sensitivity of a previous history of thrombosis to predict PE was low, 25 % (2/8 men), 4 % (1/24 women).ConclusionsOf 154 men hospitalized for PE, 8 (5 %) used TT, and of 193 women, 24 (12 %) used ET. Our data suggests that PE is an important complication of TT in men and ET in women, in part reflecting an interaction between familial and acquired thrombophilia and exogenous hormone use.

BackgroundPCSK9 inhibitor therapy has been approved by the FDA as an adjunct to diet-maximal tolerated cholesterol lowering drug therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) with suboptimal LDL cholesterol (LDLC) lowering despite maximal diet-drug therapy. With an estimated ~24million of US hypercholesterolemic patients potentially eligible for PCSK9 inhibitors, costing ~ $14,300/patient/year, it is important to assess health-care savings arising from PCSK9 inhibitors vs ASCVD cost.MethodsIn 103 patients with HeFH, and/or ASCVD and/or suboptimal LDLC lowering despite maximally tolerated diet-drug therapy, we assessed pharmacoeconomics of PCSK9 inhibitor therapy with lowering of LDLC. For HeFH diagnosis, we applied Simon Broome’s or WHO Dutch Lipid Criteria (score >8). Estimates of direct and indirect costs for ASCVD events were calculated using American Heart Association (AHA), U.S. DHHS, Healthcare Bluebook, and BMC Health Services Research databases. We used the ACC/AHA 10-year ASCVD risk calculator to estimate 10-year ASCVD risk and estimated corresponding direct and indirect costs. Assuming a 50 % reduction in ASCVD events on PCSK9 inhibitors, we calculated direct and indirect health-care savings.ResultsWe started 103 patients (58 [56 %] women and 45 [44 %] men), on either alirocumab (62 %) or evolocumab (38 %), median age 63, BMI 29.0, and LDLC 149 mg/dl. Of the 103 patients, 28 had both HeFH and ASCVD, 33 with only ASCVD, 33 with only HeFH, and 9 had neither. Of the 103 patients, 61 had a first ASCVD event at median age 55 and on best tolerated cholesterol-lowering therapy median LDLC was 137 mg/dl. In these 61 patients, total direct costs attributable to ASCVD were $8,904,361 ($4,328,623 direct, $4,575,738 indirect), the median 10-year risk of a new CVD event was calculated to be 13.1 % with total cost $1,654,758. Assuming a 50 % reduction in ASCVD events on PCSK9 inhibitors in our 61 patients, $4,452,180 would have been saved in the past; and future 10-year savings would be $1,123,345.ConclusionIn the 61 CVD patients, net costs/patient/year were estimated to be $7,000 in the past, with future 10-year intervention net costs/patient/year being $12,459, both below the $50,000/year quality adjusted life-year gained by PCSK9 inhibitor therapy.

and how many patients are investigated, given their usually subtle presentation of yellow-orange macules involving the palm creases. These are considered pathognomonic of FD, but may be confused with planar xanthoma seen in cholestasis diseases, which are usually white plaques that extend beyond the palmar creases. 4 Since FD has important cardiac 5 and dermatologic manifestations that respond well to treatment, 3 identification of FD is critical.Recognition by all physicians, especially dermatologists, of the rare diagnostic and pathognomonic physical sign of PCXs of apoE2/2 dysbetalipoproteinemia, opens the door to early diagnosis, documentation, and therapy; all focused on resolution of both cutaneous xanthomas and atherosclerotic lesions. The dermatologist is the gatekeeper for early diagnosis and treatment.

Background:Vitamin D deficiency (<32 ng/mL) is a reversible cause of statin-intolerance, usually requiring vitamin D3 (50,000-100,000 IU/week) to normalize serum D, allowing reinstitution of statins. Longitudinal safety assessment of serum vitamin D, calcium, and estimated glomerular filtration rate (eGFR) is important.Aims:Prospectively assess the safety-efficacy of vitamin D3 therapy.Materials and Methods:In 282 statin-intolerant hypercholesterolemic patients for 6 months and in 112 of the 282 patients for 12 months, with low-entry serum vitamin D (<32 ng/mL), we assessed safety-efficacy of vitamin D3 therapy (50,000-100,000 IU/week).Results:On mean (66,600 IU) and median (50,000 IU) of vitamin D3/week in 282 patients at 6 months, serum vitamin D rose from pretreatment (21—median) to 46 ng/mL (P < 0.0001), and became high (>100 ng/mL) but not toxic (>150 ng/mL) in 4 patients (1.4%). Median serum calcium was unchanged from entry (9.60 mg/dL) to 9.60 at 6 months (P = .36), with no trend of change (P = .16). Median eGFR was unchanged from entry (84 mL/min/1.73) to 83 at 6 months (P = .57), with no trend of change (P = .59). On vitamin D3 71,700 (mean) and 50,000 IU/week (median) at 12 months in 112 patients, serum vitamin D rose from pretreatment (21—median) to 51 ng/mL (P < 0.0001), and became high (>100 but <150 ng/mL) in 1 (0.9%) at 12 months. Median serum calcium was unchanged from entry (9.60 mg/dL) to 9.60 mg/dL and 9.60 mg/dL at 6 months and 12 months, respectively; P > 0.3. eGFR did not change from 79 mL/min/1.73 at entry to 74 mL/min/1.73 and 77 mL/min/1.73 at 6 months and 12 months, P > 0.3. There was no trend in the change in serum calcium (P > 0.5 for 6 months and 12 months), and no change of eGFR for 6 months and 12 months, P > 0.15.Conclusions:Vitamin D3 therapy (50,000-100,000 IU/week) was safe and effective when given for 12 months to reverse statin intolerance in patients with vitamin D deficiency. Serum vitamin D rarely exceeded 100 ng/mL, never reached toxic levels, and there were no significant change in serum calcium or eGFR.

Venous thromboembolism is uncommon after knee arthroscopy, and there are no guidelines for thromboprophylaxis in elective routine knee arthroscopy. Preoperative evaluation of common thrombophilias should provide guidance for postarthroscopy thromboprophylaxis in otherwise healthy patients who are at high risk for venous thromboembolism. This study assessed 10 patients with venous thromboembolism after total hip or knee arthroplasty. Patients were assessed if venous thromboembolism occurred within 6 months after knee arthroscopy (n=10) or total hip or knee arthroplasty (n=21). This study assessed gene mutations (factor V Leiden, prothrombin G20210A, plasminogen activator inhibitor, methylenetetrahydrofolate reductase) and serologic thrombophilias (high levels of factors VIII and XI, homocysteine, anticardiolipin immunoglobulin G and immunoglobulin M antibodies, and lupus anticoagulant; low antigenic protein C, S, and free S; and antithrombin III deficiency). The same coagulation data were obtained for normal subjects (n=110). The major thrombophilias in the arthroscopy group were factor V Leiden heterozygosity (40%), high factor VIII level (50%), and high homocysteine (30%). The respective values in control subjects were 2% (P=.0004), 7% (P=.0011), and 5% (P=.02). When the arthroscopy group was compared with the 21 patients who had venous thromboembolism after total hip or knee arthroplasty, the sole difference was factor V Leiden heterozygosity, which was 40% vs 0%, respectively (P=.007). Although venous thromboembolism after knee arthroscopy is uncommon, to identify high-risk patients and guide postoperative thromboprophylaxis, the authors suggest routine preoperative measurement of 3 common familial thrombophilias: factor V Leiden, factor VIII, and homocysteine. [Orthopedics. 2016; 39(6):e1052-e1057.].